Fluridone Hum an H ea lth Risk Assess ment DP No

. 423464

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: J an u a r y 20, 20 16 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION

SUBJECT: F lurid onc

. Human Hea l th Ri sk Assessment for R eg i s tration R ev iew and to Suppor t the Re g i stra ti o n of th e Use on Cot to n.

P C Co d e: I 12900 DP Barc ode: 423464

D ec i s ion No.: 494948 Re g i s tration No.: 67690-NEW

Petiti o n No.: 4F8308 Re g ulat o r y Act i on: Registration Review

Ri s k A ss e ss m e n t T y p e: Single Chemica l Aggrega t e Case No.: 7200

TXR No.: NA CAS No.: 59756-60-4

MRID No.: NA 40 CFR: 180 .420

FROM:

# Ronni**.Beve rJr.** **PhD DAB** **~** .i';

# ~~-~A Alexa ndra Gave l ek, Biologist 

# 1 h._ M\

Uma Habiba

, Che mi st

### ~ K elly M. Lowe

, Environmental Scie n tist**~** Risk Assess m e nt Branch V N II

H ealth Effects Division (7509P)**~**

Austin Wray, Toxico l ogist

# ~ /1.J'

# ~ Ri s k Assessment Bran c h I V 

## 1 )----

H ea lth Effec t s Division (7509P)

## ~/ 

## j 

# J) (/ \

THROUGH: Michael Metzger, B ranc h Chief, Risk Assessment Bran c h YN II

## ~ {t /) JJ1 " } i

, . Donna Dav i s , Risk Assessmen t Review Co mmitt ee D esignated eviewe r**U~** Anna Lowit

, Risk Assess m ent R eview Committee D esignated R ev i ewe r (} 

## /!._ ) /

H ealth Effects Division (7509P) 

# '-'(D**~**

TO: Sara h Meadows, Risk Mana ge r Reviewe r
K ath r y n Montague, Risk Mana ge r
R eg i stra ti o n Divi s ion

Le i gh Rimmer, Chemical Review Manager

Tom Myers

, Team Leade r Kevin Costello

, Bran ch Chief

Pesticide Re-Evaluation Di v i s i on

P age I of 83Fluridone Human Health Risk Assessment DP No. 423464

Page 2 of 83 1.0 Executive Summary

................................ ................................ ................................ ........... 4
2.0 HED Recommendations

................................ ................................ ................................ .... 7
2.1 Data Deficiencies

................................ ................................ ................................ ............ 7
2.2 Tolerance Considerations

................................ ................................ .............................. 7
2.2.1 Enforcement Analytical Method

................................ ................................ ............ 7

2.2.2 Recommended Tolerances

................................ ................................ ....................... 7

2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ . 9

2.2.4 International Harmonization

................................ ................................ ................ 10

2.3 Label Recommendations

................................ ................................ .............................. 10
2.3.1 Recommendations from Residue Reviews

................................ ........................... 10

2.3.2 Recommendations from Occupational Assessment

................................ ............ 10

2.3.3 Recommendations from Residential Assessment

................................ ................ 11

3.0 Introduction

................................ ................................ ................................ ...................... 11
3.1 Chemical Identity

................................ ................................ ................................ ......... 11
3.2 Physical/Chemical Characteristics

................................ ................................ ............. 11
3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 11
3.4 Anticipated Exposure Pathways

................................ ................................ ................. 13
3.5 Consideration of Environmental Justice

................................ ................................ .... 14
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 14
4.1 Toxicology Studies Available for Analysis

................................ ................................ . 14
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

............................. 15
4.2.1 Dermal Absorption

................................ ................................ ................................ ... 15
4.3 Toxicological Effects

................................ ................................ ................................ .... 16
4. 4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 17
4.4.1 Completeness of the Toxicology Database

................................ .............................. 17
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 18
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 18
4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 18
4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 1 8
4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 18
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

..... 20
4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 20
4.6 Endocrine Disruption

................................ ................................ ................................ ... 22
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 23
5.1 Metabolite/Degradate Residue Profile

................................ ................................ ....... 23
5.1.1 Summary of Plant and Animal Metabolism Studies

................................ .......... 23

5.1.2 Summary of Environmental Degradation

................................ ........................... 23

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ..... 24

5.1.4 Residues of Concern Summary and Rationale

................................ .................... 24

5.2 Food Residue Profile

................................ ................................ ................................ .... 25
5.3 Water Residue Profile

................................ ................................ ................................ .. 26
5.4 Dietary Risk Assessment

................................ ................................ .............................. 27Fluridone Human Health Risk Assessment DP No. 423464

Page 3 of 83 5.4.1 Description of Residue Data Used in Dietary Assessment

................................ . 27

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ............ 27

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............ 27

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........ 27

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ .......... 28

5.4.6 Summary Table

................................ ................................ ................................ ...... 28

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 28
6.1 Residential Handler Exposure

................................ ................................ .................... 28
6.2 Residential Post

- Application Exposure

................................ ................................ ...... 31
6.3 Residential Risk Estimates for Use in Aggreg ate Assessment

................................ .. 32
6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ 32
6.5 Spray Drift

................................ ................................ ................................ .................... 32
7.0 Aggregat e Exposure/Risk Characterization

................................ ................................ .. 35
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 35
7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 35
7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 35
7.4 Chronic Aggregate Risk

................................ ................................ .............................. 36
7.5 Cancer Aggregate Risk

................................ ................................ ................................ 36
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 36
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 36
9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 36
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 43
9.2.1 Dermal Post

- application Risk

................................ ................................ ............... 43

9.2.2 Inhalation Post

- application Risk

................................ ................................ .......... 43

Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 46
A.1 Toxicology Data Requirements

................................ ................................ ................... 46
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 47
A.3 Hazard Identification and Endpoint Selection

................................ .......................... 52
A.4 Executive Summaries

................................ ................................ ................................ ... 54 Appe ndix B. Physical/Chemical Properties

................................ ................................ ............. 71 Appendix C. Review of Human Research

................................ ................................ ................ 72 Appendix D. International Tolerances and MRLs

................................ ................................ .. 73 Appendix E. NMF Exposure and Risk Assessment

................................ ................................ 75Fluridone Human Health Risk Assessment DP No. 423464

Page 4 of 83 1.0 Executive Summary

The Registration Division (RD) has requested an assessment of human health risk to support the proposed new use of fluridone on pre

- emergent cotton and the Pestici de Re

- evaluation Division (PRD) has requested a draft assessment of human health risk to support the registered uses of

fluridone (1

- methyl

- 3

- phenyl

- 5

- [3

- trifluoromethyl) phenyl]

- 4(1 H )

- 5

- [3

- (trifluoromet hyl)phenyl]

- 4(1 H )

- pyridinone) as part of Registrati on Review

.

Fluridone is a systemic herbicide used on ponds (including a homeowner use), lakes, reservoirs, irrigation canals, drainage canals, and rivers. It inhibits carotene synthesis, which causes the loss of chlorophyll. Current labels permit single treatments of up to a concentration of 90 ppb for whole lake treatments and 150 ppb for partial lake treatments, with a maximum cumulative application concentration of 150 ppb p er lake weed growth cycle. Water from areas treated with

fluridone can be used for the ir rigation of crops and pastures or used as drinking water for livestock. Tolerances are currently established for inadvertent residues of fluridone in numerous crops, livestock commodities, fish and crayfish as a result of the aquatic uses. There is also a proposed new use of fluridone as a pre

- emergent (direct soil) treatment to cotton. HED has determined that the current tolerance of 0.1 ppm for inadvertent residues of fluridone in cotton is adequate to cover any residues that may occur in cotton commoditi es as a result of the proposed

direct soil use for cotton.

Humans may be exposed to fluridone in food and drinking water. In a residential setting, applicators may be exposed while applying the pesticide to residential ponds. There is also potential fo r residential post

- application exposure to fluridone while swimming in treated water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is negligible post

- applic ation exposure for workers based on the registered and proposed use.

The toxicology database is adequate to assess current and proposed uses for fluridone; the subchronic neurotoxicity and inhalation studies were waived by the Hazard and Science Policy Council (HASPOC). The liver and kidneys were identified as the primary target organs based on a multitude of organ specific effects noted across the toxicity database. All species exhibited indications of liver toxicity that were often accompanied by body weight effects. Mice were the most sensitive species examined

, and dogs were the most tolerant. Rat sensitivity was comparable (chronic exposure) to or slightly less (subchronic exposure) than mice; however, rats were the only species to exhibit minor kidn ey effects in addition to liver and body weight toxicity. Progression of toxicity from subchronic to chronic exposures was not observed in mice and was limited (2

- fold difference) in rats. No evidence of fetal sensitivity was observed in rats

or rabbits. B ody weight effects in the F 2 rat offspring during the lactation period were suggestive of susceptibility in the young. However, the effects were isolated to the F 2 offspring; body weight

of the F 2 offspring returned to control levels after the lactation pe riod ; and no subsequent evidence of susceptibility was observed in progeny of the F 2 generation. Furthermore, the offspring effects occurred at doses 2 to 4.5 times higher than the target organ and body weight toxicity noted in adult rodents in other studi es

. B ehavioral anomalies, physiological effects, and locomotor impairment consistent with neurotoxicity were only observed following acute gavage exposure to doses that likely exceeded linear pharmacokinetics and were at least 13 to 26 timesFluridone Human Health Risk Assessment DP No. 423464

Page 5 of 83 higher than the lowest doses causing liver and kidney effects in rodents. No signs of neurotoxicity were identified in the rest of the toxicity database. Toxicity from repeated dose dermal exposures was limited to irritation effects on the skin (erythema, desquamation, epidermal fissures). No evidence of immunotoxicity, mutagenicity, or carcinogenicity were noted in the toxicity database.

An acute population adjusted dose (PAD) for all populations was selected from an acute neurotoxicity study in rats bas ed on decreased ambulatory counts and the prevalence of functional observational battery (FOB) anomalies in males and females. No acute effect specific to child bearing females was observed in the submitted studies; therefore, no acute endpoint was

selecte d for the female 13

- 49 subpopulation. A chronic PAD was selected from a 2 year mouse cancer study based on increased alkaline phosphatase activity and increased incidence of hepatocellular hyperplasia. A slightly lower NOAEL was noted in the rat combined c hronic toxicity/carcinogenicity study; however, this fact was considered to be due to dose

- selection. Considering the mouse and rat exhibited comparable sensitivity to chronic exposure, the mouse point of departure (POD) was protective of the chronic effec ts in the rat. The same endpoints from the 2 year mouse study were selected for short

- and intermediate

- term incidental oral, dermal and inhalation exposures, because m ice were the most sensitive species and there was no progression of toxicity from subchro nic to chronic exposures in mice. An upper bound dermal absorption factor of 39% was used in the dermal assessment to account for route to route extrapolation. In the inhalation assessment, absorption was assumed to be 100% using the oral endpoint. An unc ertainty factor of 100x was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation). The Food Quality Protection Act safety factor (FQPA SF ) was reduced to 1X for fluridone because the deve lopmental and offspring effects are well defined and have clear no observed adverse effect levels (NOAEL) and lowest observed adverse effect levels (LOAEL), PODs selected for risk assessment are protective of the developmental and offspring effects, and th ere are no residual uncertainties in the fluridone exposure or toxicity database.

Acute and chronic unrefined dietary assessments were conducted for fluridone that incorporated

tolerance

- level residues, 100% crop treated, and default processing factors. Modeled estimated drinking water concentrations (EDWCs) were directly incorporated into the assessment as point estimates. Acute and chronic dietary (food and drinking water) exposure and risk estimates were not of concern to HED for the general US populat ion and all population subgroups (i.e., all risk estimates were <100% of the population

- adjusted dose).

The residues of concern for tolerances and risk assessment purposes for both food and livestock is the parent fluridone. The a ppropriate tolerance lev el would be 0.1 ppm for all crops for which there were no direct uses, except for animal feed non

- grass group 18 and grass forage; a tolerance of 0.15 ppm would be appropriate for those livestock feed items. No residue data were

submitted with the Section 3 request for use on cotton

. Given the absence of fluridone residues

in cottonseed and w hole cotton plants from geographically appropriate field trials, it can be concluded that residues of fluridone from the proposed S ection 3 use would not exceed the

cu rrent tolerance level of 0.1 ppm for cottonseed, undelinted. HED has recommended that a tolerance for fluridone on cotton gin byproducts also be established at 0.1 ppm.Fluridone Human Health Risk Assessment DP No. 423464

Page 6 of 83 The proposed new use on cotton is not anticipated to result in residential exposures; however, the existing aquatic uses of fluridone were assessed as part of Registration Review

. The residential

handler assessment assessed dermal and inhalation exposure of homeowners applying fluridone to ponds; there were no risks of concern for residential handlers (i.e., all combined margins of exposure ( MOEs ) ≥ 100) . The residential post

- application exposure assessment assessed adults

and children (3 to < 6 years old) who may be exposed to fluridone while swimming in treated

water (dermal, inh alation and incidental ingestion exposure routes) . There were no risks of

concern for swimmers for the individual routes (i.e., all fluridone MOEs ≥ 100) . Since all the routes of exposure are based on the same effect, the exposures can be combined across routes

. The combined MOEs for adults and children (3 to < 6 years old) are also not of concern (i.e., all

fluridone combined MOEs ≥ 100)

.

The acute aggregate risk is equivalent to the acute dietary risk estimates. The acute dietary exposure estimates for fluridone (food and drinking water) ar e not of concern to HED (<100%

a PAD) for the general U.S. population an d all population subgroups

. For the short

- term aggregate risk assessment, potential residential exposures ( dermal, inhalation and incidental

i ngestion from swimming in treated waters) were combined with chronic dietary exposures. The

short

- term aggregate MOEs for fluridone for adults and children are greater than the level of concern ( LOC ) and are

, therefore

, not of concern. Intermediate

- term residential exposures are not likely because of the intermittent residential exposure to fluridone ; t herefore , an intermediate

- term aggregate risk assessment is not required. There are no chronic residential exposure scenarios; therefore, the chronic aggregate risk is equival ent to the chronic dietary risk

estimate . The chronic dietary (food and drinking water) exposure estimates for fluridone are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups

.

Occupational exposure is anticipated from both the proposed cotton use, as well as the existing aquatic uses. Occupational handlers may be exposed via dermal and inhalation routes

, whi le mixing/loading and applying the products to aquatic areas or to cotton. There were no ri sks of concern for occupational handlers making applications to cotton via groundboom equipment with the proposed label

- required clothing

. There are risk estimates of concern for some of the registered aquatic use scenarios. Occupational handler combined dermal and inhalation MOEs range from 6.1 to 18,000 with baseline clothing (single layer clothing, shoes plus socks, no gloves, and no respirator for all scenarios

, except aerial applicator where engineering controls were used)

. The scenario of mixing/loading/applying with a handwand sprayer to aquatic sites

was not of concern with the addition of gloves. The scenario of mixing/loading/applying product with backpac k sprayer to aquatic sites was not of concern with the addition of double layer clothing and gloves. For aquatic use applications, the current product labels do not require PPE

. Because of the risk concerns identified in the occupational handler assessme nt for the aquatic

uses , it is recommended that the product labeling for aquatic uses direct applicators to wear long

sleeved shirt

, long pants

, shoes plus socks , as well as additional PPE , such as gloves and a coverall (i.e., double layer of clothing) for applications with handheld equipment

.

There is potential non

- occupational exposure via spray drift from the proposed agricultural use on cotton. The spray drift assessment assessed ad ults and children (1 to <2 years old) who may be exposed to residues of fluridone on a lawn next to a field that was previously treated withFluridone Human Health Risk Assessment DP No. 423464

Page 7 of 83 fluridone. There were no risks of concern for exposures from spray drift at the field edge (dermal and incidental oral MOEs ≥ 100 at the edge of the field)

.

As the proposed use is on pre

- plant or pre

- emergent cotton, occupational post

- application dermal exposure to residues on foliage is expected to be negli gi ble . The restricted entry interval ( REI ) of

24 hours on th e proposed label for the cotton use is adequate and meets the minimum WPS requirements. Since the currently registered uses of fluridone are in aquatic environments, there are no occupational post

- application activities which would result in occupational e xposures from treated bodies of water. As application to aquatic/de

- watered areas do not fall under the purview of WPS

, and worker re

- entry exposure is considered to be negligible, an REI is not applicable for these uses.

Based on the Agency’s current pr actices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for fluridone at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for fluridone.

2.0 HED Recommendations

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available in the Pesticide Analytical Manual (PAM) Volume II for the enforcement of tolerances for residues of fluridone in plant commodities, including cotton. The plant method is a n HPLC method (originally submitted as method AM

- AA

- CA

- RO52

- AA

- 755). The limit of quantitation is 0.05 ppm. There are a lso PAM Vol II methods for fluridone in livestock commodities (LOQ = 0.05 ppm) and for residues of fluridone and the metabolite

, 4

- hydroxy

- fluridone

, in fish (LOQ = 0.10 ppm and 0.05 ppm, respectively).

2.2. 2 Recommended Tolerances

HED has reviewed the p etition request to determine the appropriate tolerances which are to be

established for the res idues of fluridone . The recommended t olerance expression is as follows;

(a) General. (1) Tolerances are established for residues of the herbicide fluridone, including its metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance with the tolerance levels specified in this paragraph is to be

determined by measuring only the only fluridone, 1

- methyl

- 3

- phenyl

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1 H )

- pyridinone, in or on the commodity.Fluridone Human Health Risk Assessment DP No. 423464

Page 8 of 83 Commodity Established/Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments Correct Commodity Definition Crayfish 0.5 0

Fish 0.5 0

(2) Tolerances are established for residues of the herbicide fluridone, including its metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only fluridone, 1

- methyl

- 3

- phenyl

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1 H )

- pyridinone, in or on the commodity.

Commodity Established/Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments Correct Commodity Definition
Cotton, undelinted seed 0.10 0.1 Cotton, gin byproducts None 0.1
Cattle, fat 0.05 Cattle, kidney 0.1 0
Cattle, liver 0.1 0
Cattle, meat 0.05 Cattle, meat byproducts 0.05 Egg 0.05
Goat, fat 0.05 Goat, kidney 0.1 0
Goat, liver 0.1 0
Goat, meat 0.05 Goat, meat byproducts 0.05 Hog, fat 0.05 Hog, kidney 0.1 0 Hog, liver 0.1 0 Hog, meat 0.05 Hog, meat byproducts 0.05
Horse, fat 0.05 Horse, kidney 0.1 0
Horse, liver 0.1 0
Horse, meat 0.05
Horse, meat byproducts 0.05

Milk 0.05 Poultry, fat 0.05 Poultry, kidney 0.01 Poultry, liver 0.01 Poultry, meat 0.05 Poultry, meat byproducts 0.05 Sheep, fat 0.05 Sheep, kidney 0.1 0 Sheep, liver 0.1 0 Sheep, meat 0.05 Sheep, meat byproducts 0.05

(d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the herbicide fluridone, including its metabolites and degradates, in or on theFluridone Human Health Risk Assessment DP No. 423464

Page 9 of 83 irrigated crop commodities and crop groupings in the table in this paragraph, resulting from use of irrigation water containing residues of 0.15 parts per million following applications of fluridone on or around aquatic sites. Where tolerances are established at higher levels from other uses of fluridone on the crops in the table in this paragraph, the higher tolerance also applies to residues in or on the irrigated commodity. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only fluridone, 1

- methyl

- 3

- pheny l

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1 H )

- pyridinone, in or on the commodity.

Commodity Established/Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments Correct Commodity Definition
Animal feed, non

- grass, group 18 0.15

Avocado 0.1 0 Berry, group 13 0.1 0
Cotton, undelinted seed 0.1 0 Cranberry 0.1 0 Fruit, citrus, group 10 0.1 0 Fruit, pome, group 11 0.1 0 Fruit, stone, group 12 0.1 0 Grain, cereal, forage, fodder and straw, group 16 0.1 0

Grain, cereal, group 15 0.1 0 Grape 0.1 0 Grass, forage 0.15 Hop, dried cones 0.1 0 Nut, tree, group 14 0.1 0

Okra 0.1 0 Strawberry 0.1 0 Vegetable, brassica, leafy, group 5 0.1 0 Vegetable, cucurbit, group 9 0.1 0 Vegetable, fruiting, group 8 0.1 0 Vegetable, leafy, except brassica, group 4 0.1 0 Vegetable, leaves of root and tuber, group 2 0.1 0 Vegetable, legume, group 6 0.1 0 Vegetable, root and tuber, group 1 0.1 0

Upon establishment of the tolerances listed above, tolerance listings for cotton undelinted seed in 180.420(b) and 180.420(d) should be revoked since it is included in the new listing.

2.2. 3 Revisions to Petitioned

- For Tolerances

HED agrees with the petitioner that the proposed tolerance for fluridone on cotton, undelinted

seed should remain at the current 0.1 ppm level; that level is adequate to cover any residues that may result from the proposed direct application to cotton.

The cotton, undelinted seed tolerance of 0.1 ppm should be added to 40 CFR 180.420 (a) general

section. The toleranc e of 0.1 ppm for cotton, undelinted seed listed in 40 CFR 180.420 (d) for inadvertent residues (from treated irrigation water) should be removed. The cotton, undelintedFluridone Human Health Risk Assessment DP No. 423464

Page 10 of 83 seed tolerance of 0.1 ppm in the 40 CFR 180.420 section (b) Section 18 emergency exempt ions
should also be removed.

The petitioner did not propose a tolerance for residues of fluridone on cotton gin byproducts. HED has recommended that a tolerance for fluridone on cotton gin byproducts be established at 0.1 ppm. A cotton gin byproduct toler ance is needed to cover this cotton raw agricultural commodities ( RAC ) . There are no other differences between the requested and recommended

tolerances.

The petitioner did not propose tolerances for fluridone on cotton processed commodities. HED
agrees t hat separate tolerances for cotton processed commodities are not required based on nondetectable residues in cotton RACs in exaggerated rate studies. The residue definition under 40 CFR 180.420 (a) needs slight modification to be consistent with the guida nce on tolerance expressions (S. Knizner, 5/27/09). The appropriate language is described below.

(2) Tolerances are established for residues of the herbicide fluridone, including its metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only fluridone, 1

- methyl

- 3

- phenyl

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1 H )

- pyridinone, in or on the commodity.

2.2.4 International Harmonization

There are no Codex, Mexican, and/or Canadian maximum residue limits (MRLs) established for the residues of fluridone. Therefore, international harmonization is not an issue for

consideration. Refer to Appendix D for a summary of international tolerances and MRLs.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None.

2.3.2 Recommendations from Occupational Assessment

Proposed Cotton Use : No label recommendations.

Registered Aquatic Use : Alth ough aquatic applications do not fall under the purview of the Worker Protection Standard (WPS), HED recommends that product labeling direct applicators to wear long

- sleeved shirt and long pants and shoes plus socks. Because of the risk concerns

identifie d in the occupational handler assessment, it is recommended that the product labeling fo r aquatic uses require handlers to wear additional PPE

.Fluridone Human Health Risk Assessment DP No. 423464

Page 11 of 83 2.3.3 Recommendations f rom Residential Assessment

None.

3.0 In troduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

. Chemical Structure

Empirical Formula C 19 H 14 F 3 NO

Common Name Fluridone

Company experimental name

IUPAC name 1

- methyl

- 3

- phenyl

- 5

- (α,α,α

- trifluoro

- m

- tolyl)

- 4

- pyridone

CAS Name 1

- methyl

- 3

- phenyl

- 5

- [3

- (trifluoromethyl)phenyl]

- 4(1 H )

- pyridinone

CAS Registry Number 59756

- 60

- 4

End

- use product/EP EL171, SP1621

Chemical Class Pyridazone Herbicide

Known Impurities of Concern N/A

3.2 Physical/Chemical Characteristics

Fluridone is an off

- white crystalline solid with a melting point of 154

- 155 o C and a bulk density of 1.4 g/ cm 3 (pyconometer method). It has a log octanol/water partition coefficient of 2.54 and a vapor pressure of <9.77 × 10

- 8 torr at 25 o C. Fluridone in the environme nt is not persistent or mobile (K d range from 5.56 to 70.3 ml/gram). Fluridone is minimally soluble in water (8.3 mg/L) and soluble in organic so lvents (0.5 to >10 mg/ml). See Table B1 in A ppendix B for the physico

chemical properties of fluridone.

3.3 P esticide Use Pattern

Proposed Use on Cotton Table 3.3.1 provides a summary of the proposed cotton use. The proposed use is for a liquid formulation to be applied via groundboom equipment at a maximum rate of 0.3 lb ai/A. The proposed product label for the pre

- emergent cotton use directs applicators and other handlers to wear long sleeved shirt, long pants, chemical

- resistant gloves, shoes plus socks and protective

eyewear. The restricted entry interval (REI) on the proposed label for cotton is 24 hours

.Fluridone Human Health Risk Assessment DP No. 423464

Page 12 of 83 Registered Aquatic Uses Table 3.3.2 provides a summary of the registered aquatic uses of fluridone. The end

- use products registered for use in aquatic settings are formulated as liquids, granulars, and water dispersible granulars (WDGs). In aquatic settings, fluridone can be applied: (1) via aerial, boom or handheld applications to ponds/lakes at a maximum application rate of 0.4 lb ai/A

- ft; (2) via direct metering to moving water at a maximum rate of 0.11 lb ai/A

- ft; (3) via handheld equipment to st atic canals at a maximum rate of 2 lb ai/A; and (4) via open pour to residential ponds at a maximum rate of 0.12 lb ai/A

- ft. The registered product labels for the aquatic uses do not require specific clothing or any personal protective equipment ( PPE )

. T he aquatic labels do

not include a REI statement.

Table 3.3. 1. Summary of Directions for Proposed Use s of Fluridone

.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic. Rate (lb ai/A) PHI (days) Use Directions and Limitations

Cotton

Pre

- plant/pre

emergent
Foliar Broadcast

Groundboom Soluble

Concentrate [67690

- NEW] 0.3 (pre

- plant, fine

to medium texture soil) 1 0.3 N/A Do not apply by air or irrigation system. Apply prior to planting or prior to emergence

of cotton. A t least 0.5 inches of rain or irrigation must occur prior to planting to

activate a.i. in soil. Use an alternative herbicide after two years of application. Avoid drift to all other crops and non

- target a reas. Apply when the potential for drift to adjacent

sensitive areas is min i mal.

Table 3.3. 2. Summary of Directions for Existing Aquatic Uses of Fluridone

.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic. Rate (lb ai/A) PHI (days) Use Directions and Limitations

Aquatic Sites

Broadcast, Metering Granular [8959

- 58] [67690

- 3] [67690

- 12] [67690

- 21] [67690

- 32] [67690

- 45] [61842

- 29] [81927

- 50] 90 ppb: 7.7 fl oz /

acre

- foot = 0.24 lb

ai/acre

- foot 150 ppb: 13 fl oz /

acre

- foot = 0.4 lb

ai/acre

- foot; 2 qts/acre = 2 lb ai/acre; Moving water:

maintain

concentration of up to 40 ppb N/A 90 ppb in ponds, 150 ppb in lakes and reservoirs; Static/dry canals: 2 qts/acre;

Mov ing water:

maintain

concentration of up to 40 ppb N/A Do not apply to waters less than 2 ft deep. Do not apply to water used for hydroponic farming. Do not use water treated with this product for irrigation in greenhouses/nursery plants.

Direct Application Ready

- to

- use [8959

- 59] [67690

- 48] [61842

- 28] [81927

- 51] Aquatic weed: 1 qt/acre

- foot = 0.08

lb ai/acre

- foot

Watermeal: 1.5 qt/acre

- foot

= 0.12 lb ai/acre

foot N/A Aquatic weeds in Ponds: 1 qt/acre

foot

Watermeal in ponds: 1.5 qts/acre

- foot N/A Do not apply through irrigation system. Do not use water treated with product to irrigate crops, turf, and plants for 30 days. Do not use water treated with this product to irrigate seedlings/new plantings for 60 days. Must stay in contact with aquatic weeds for at least 45 days.Fluridone Human Health Risk Assessment DP No. 423464

Page 13 of 83 Table 3.3. 2. Summary of Directions for Existing Aquatic Uses of Fluridone

.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic. Rate (lb ai/A) PHI (days) Use Directions and Limitations

3 qt s/acre

foot/season No swimming, water consumption

restrictions. Broadcast, metering [42750

- 280] Liquid 90 ppb: 7.7 fl oz /

acre

- foot = 0.24 lb

ai/acre

- foot 150 ppb: 13 f l oz /

acre

- foot = 0.4 lb

ai/acre

- foot N/A 90 ppb in ponds 150 ppb in

lakes/reservoirs 20 ppb near potable water

intakes N/A Do not apply through irrigation system. Do not used treated water for hydroponic farming. Do not use to irrigate greenhouse/nurs ery. If 150 ppb or less, water may be used for drinking, watering livestock/pets, fishing, and swimming. Broadcast, metering Liquid

Concentrate [67690

- 4] [67690

- 30] [61842

- 11] [81927

- 45] 90 ppb: 7.7 fl oz /

acre

- foot = 0.24 lb

ai/acre

- foot 150 ppb: 13 fl oz /

acre

- foot = 0.4 lb

ai/acre

- foot N/A 90 ppb in ponds 150 ppb in

lakes/reservoirs 20 ppb near potable water

intakes N/A Do not apply through irrigation system. Do not used treated water for hydroponic farming. Do not use to irrigate greenhouse/nurse ry. If 150 ppb or less, water may be used for drinking, watering livestock/pets, fishing, and swimming. Broadcast, metering Liquid

Concentrate [67690

- 54] 90 ppb: 0.48 gal/

acre

- foot = 0.24 lb

ai/acre

- foot 150 ppb: 0.81 gal/

acre

- foot = 0.4 lb

ai/ acre

- foot N/A 90 ppb in ponds, 150 ppb in lakes

and reservoirs N/A Do not apply through irrigation system. Do not used treated water for hydroponic farming. Do not use to irrigate greenhouse/nursery. If 150 ppb or less, water may be used for drinking, wa tering livestock/pets, fishing, and swimming. Broadcast, metering Solid [67690

- 61] 90 ppb: 0.48 gal/

acre

- foot = 0.24 lb

ai/acre

- foot 150 ppb: 0.81 gal/

acre

- foot = 0.4 lb

ai/ acre

- foot N/A 90 ppb in ponds, 150 ppb in lakes

and reservoirs N/A Do not apply through irrigation system. Do not used treated water for hydroponic farming. Do not use to irrigate greenhouse/nursery. If 150 ppb or less, water may be used for drinking, watering livestock/pets, fishing, and swimming.

3.4 Anticipated Ex posure Pathways

The Registration Division (RD) has requested an assessment of human health risk to support the proposed new use of fluridone on pre

- emergent cotton

, and the Pesticide Re

- evaluation Division (PRD) has requested an assessment of human health risk to support the registered uses of fluridone as part of Registration Review

. Humans may be exposed to fluridone in food and drinking water. Fluridone is currently registered as an aquatic herbicide ; therefore, residues of fluridone may get into food at low levels when treated water is used to irrigate crops. Also, fluridone is proposed for p re

- emergent treatment of cotton , resulting in levels which do not exceed those currently established based on use of treated irrigation water in cotton . T hese

t reatments may result in fluridone reaching surface and ground water sources of drinking water. In a residential setting, applicators may be exposed to fluridone while applying the pesticide to residential ponds. There is also potential for residential po st

- application exposure to fluridone while swimming in treated water. In an occupational setting, applicators may be exposed to
fluridone while handling the pesticide prior to application, as well as during application. There is negligible post

- applicati on exposure for workers based on the registered and proposed uses

.Fluridone Human Health Risk Assessment DP No. 423464

Page 14 of 83 Risk assessments have been previously prepared for the existing uses of fluridone (Dole, 2004

, D306456). This risk assessment considers all of the aforementioned exposure pathways and includes the newly proposed use of fluridone on cotton.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf )

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a resi dential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all r egistered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or p laying on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm

wo rkers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The fluridone toxicity database is adequate for risk assessment (Appendix A). The following studies were considered in designating the points of departure (PODs) for each exposure

scenario:

• 90 day oral toxicity study

– rat and mouse

• 21 day dermal toxicity study

– rabbit

• Prenatal developmental toxicity study

– rat and rabbit

• Multi

- generation reproduction and fertility toxicity study

– rat

• 1 year chronic toxicity study

– dog

• 2 year chronic toxicity/carcinogenicity study

– rat and mouse

• Mutagenicity battery

• Acute neurotoxicity study (ACN)

– rat

• Metabolism pharmacokineti cs study

– rat

• Immunotoxicity studyFluridone Human Health Risk Assessment DP No. 423464

Page 15 of 83 HASPOC waived the subchronic neurotoxicity study (Rury, 2013, TXR 0056853) using a weight

of evidence (WOE) approach that considered the low incidence of neurotoxic effects in the ACN study

, the high doses required to elicit behavioral changes in the ACN study , and the protective nature of the previous ly selected PODs. HASPO C also waived the subchronic inhalation study ( Leshin, 2015, TXR 0057221 ) using a WOE approach that considered the physical/chemical properties of f luridone including low vapor pressure, low acute inhalation toxicity (Category III), and the large short

- and intermediate

- term inhalation MOEs calculated with previously selected

POD s. No deficiencies exist in the database for the parent compound.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Three studies were submitted detailing the fluridone ADME profile. In each study male and female rats were administered a single or multiple fluridone doses via oral gavage at dose levels ranging from 10

- 1000 mg/kg/day.

The ADME profile did not vary significantly between males and females

. Ingested fluridone was rapidly and almost completely absorbed into the systemic circulation. Elimination was equally rapid and the rate was dose

- dependent. In one study, fecal and urinary excretion following acute and repeated dose 10 mg/kg oral exposures were nearly identical (80

- 90% in 24 hours, 90

- 97% in 48 hours) and faster than elimination of a single 1000 mg/kg oral dose (~30% in 24 hours, 82

- 88% in 48 ho urs). A similar trend was observed in another study: single low dose exposures ranging from 10

- 500 mg/kg were eliminated more quickly (67

- 89% in excreta after 24 hours; 86

- 98% in 72 hours) than a single dose exposure to 1000 mg/kg (43

- 49% in excreta after 24 hours;

78

- 87% in 72 hours). Fluridone was eliminated predominately in the feces (68

- 92%) and, to a lesser extent, the urine (4

- 19%). The release of fluridone in expired air was insignificant relative to the other elimination pathways (<0.01%). The majo r component in the excreta of rats exposed to 10 mg/kg were fluridone metabolites produced primarily by ring hydroxylation and N

demethylation (single low dose = 3.9

- 5.1% parent, 59.4

- 66.5% metabolite; multiple low doses =

3.9

- 7.3% parent, 54.7

- 57.1% metab olite). The opposite was true in rats exposed to 1000 mg/kg. At this high dose metabolic pathways became saturated and the parent compound was the dominant chemical species (52.9

- 60.3% parent, 30.3%

- 33.8 metabolite) in the excreta. Fourteen
metabolites wer e identified in the feces and urine (detailed in section A.4.8) . On average, 61

- 66% of the total radioactivity was present in the bile 48 hours after administration of a 100 mg/kg oral dose. The fluridone fraction in the bile consisted of unidentified high ly polar metabolites (37% of administered dose [AD]), parent ( 8% of AD )

, and the 4

- hydroxyphenyl fluridone (6% of AD ).

The percentage of fluridone in the tissues ( < 1%) was minimal relative to the eliminated fraction. The highest tissue concentrations wer e observed in the liver and kidney (~0.3

- 0.7%) and the highest tissue to plasma ratios were found in the liver, kidney, ileum, and colon. The concentration accumulated in tissues was proportional to the dose.

4.2.1 Dermal Absorption No dermal absorpti on study was submitted by the registrant ; therefore, a dermal absorption factor (DAF) of 39% was calculated using the ratio of the 21 day rabbit dermal toxicity study NOAEL (768 mg/kg/day) and the rabbit developmental toxicity study LOAEL (300 mg/kg/day)

.Fluridone Human Health Risk Assessment DP No. 423464

Page 16 of 83 No systemic effects were observed at the highest dose tested (768 mg/kg/day) in the rabbit dermal study thus the estimated DAF represents the upper bound limit of dermal absorption for fluridone. The DAF of 39% will be applied to convert oral doses to der mal equivalent doses, since an oral toxicity study was selected to assess risks from dermal exposures (see Section 4.5.1)

DDDDDD = 300 mmmm kk / dddddd

768 mmmm kk / dddddd × 100 = 39%

4.3 Toxicological Effects

Fluridone is a systemic herbicide that inhibits phytoene desaturase, disrupting the conversion of phytoene into phytofluene in the carotenoid biosynthetic pathway causing the loss of chlorophyll (Kowalczyk

- Schrder and Sandmann 1992). The mode of action in mammals is unknown; however, the majority of the effects occurred in the liver of all species tested and in the kidneys of rats, which is consistent with the distribution profile (i.e. higher tissue concentration and higher tissue to plasma ratio) of these two organs. Mice were the most sensitive specie s to repeated dose oral exposure and their response to exposure was irrespective of duration. At doses of 25 mg/kg/day and above mice exhibited hepatocellular hyperplasia and centrilobular hypertrophy, leadi ng to increased liver weight and elevated alkalin e phosphatase activity. At slightly higher doses, rats exhibited similar liver weight and liver histopathological effects along with an increase in absolute and relative kidney weight. Although rats exhibited progression of toxicity from subchronic to chro nic exposure, the magnitude of progression was low (2

- fold difference). The lack of progression in the mouse and slight progression of toxicity with duration in the rat is supported by the similarities in clearance patterns following low single and multipl e dose exposure regimens and minimal accumulation in tissues. No incidences of liver or kidney tumors were observed in either rodent species. Dogs were more tolerant of fluridone exposure;

the onset of l iver effects (increased absolute liver weight and alk aline phosphatase activity)

occurred at a much higher dose level (400 mg/kg/day) than the other mammalian species tested.

Other s ystemic effects were observed concurrently with the liver and kidney effects in both rodents and dogs, including decreases in b ody weight and body weight gain. In all species, the onset of target organ and body weight effects were at doses that within the linear pharmacokinetic range.

In contrast, concurrence of behavioral anomalies (uncoordinated air righting reflex, muted

resp onse to touch, approach, startle and tail pinch) with impaired physiological (depressed catalepsy time) and locomotor (decreased ave rage ambulatory counts) function were observed in

rats only at acute gavage doses (650 mg/kg/day and above) that likely exce eded linear pharmacokinetics and were least 13

- 26 times above those eliciting the aforementioned kidney

and liver effects in repeated dose exposures. No s ymptoms consistent with neurotoxicity were

observed during subchronic and chronic oral exposures to mice, rats, or dogs

.

Flur i d o ne exposure was linked to increased incidences of abortions in pregnant rabbits during the last 5 days of gestatio n at 300 and 750 mg/kg/day and to l ower fetal body weig ht and skeletalFluridone Human Health Risk Assessment DP No. 423464

Page 17 of 83 malformations in developing rats at 1 000 mg/kg/day. In both mammals, concurrent maternal body weight effects likely contributed to the developmental anomalies and abortions; therefore, neither were considered evidence of fetal sensitivity

. E vidence suggestive of s usceptibility was

evident in the F 2 offspring manifesting as reduced body weight gain during lactation period and body weight on lactation day 21 at 112 mg/kg/day. However, these effects were isolated to the F 2 offspring; body weight of the F 2 offspring returned to control levels afte r the lactation period ; and no subsequent evidence of susceptibility was observed in progeny of the F 2 generation. Furthermore, the offspring effects were only observed at doses 2 to 4.5 times above those eliciting target organ and body weight toxicity in rodents in other studies

.

Fluridone was not mutagenic or carcinogenic. Acute dermal administration was minimally toxic and did not cause dermal irritation or sensitization. Likewise, systemic toxicity was not observed in repeated dermal doses up to 768 m g/kg/day; however, the longer duration dermal exposure did produce dermal irritation effects ( erythema, desquamation, epidermal fissures ) not observed in the acute exposure. Fluridone was also identified as an ocular irritant based on slight to moderate

co rneal dullness, iritis, and conjunctivitis following acute eye exposure.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

The 10x FQPA Safety Factor (FQPA SF) was reduced to 1X based on the following

considerations:

1. The toxicology and exposure databases for fluridone are complete and the toxicology studies are adequate for assessing increased susceptibility under FQPA.

2. There was no evidence of qualitative susceptibility in fetuses in the rat and rabbit developmental study. Suggestive ev idence of susceptibility was observed in the young from the F 2 population in the reproductive study during the lactation phase (based decreased body weight); however, body weight of the F 2 offspring returned to control levels after the lactation period and no evidence of susceptibility was

observed in the F 3 offspring.

3. The LOAELs and NOAELs for the rat and rabbit developmental

, and rat reproduction studies are clearly defined.

4. The endpoints selected for the assessment are pro tective of the offspring effect s

. 5. There are no residual uncertainties in the toxicology database.

6. Exposure assessments are conservative and will not under

- estimate exposure (see 4.4.4 below).

4.4.1 Completeness o f the Toxicology Database

The toxicity database is adequate to assess risk for infants and children. Two developmental studies and a three generation reproductive study are available for the parent compound. The registrant submitted an acute neurotox icity and immunotoxicity test to fulfill guideline requi rements. The subchronic neurotox icity and inhalation studies w ere waived by HASPOC (see 4.1) . No deficiencies are present in the fluridone toxicity database that would hinder

assessment of the current ly registered uses and the new use on cotton

.Fluridone Human Health Risk Assessment DP No. 423464

Page 18 of 83 4.4.2 Ev idence of N eurotoxicity

The combination of behavioral anomalies and impaired physiological and locomotor function in the ACN study were suggestive of neurotoxicity following high dose acute exposure. However, the concern for neurotoxicity arising from re gistered and proposed uses is low because: the adverse effects in the ACN study were only seen at relatively high gavage doses (650

- 2000 mg/kg/day) , which may exceed the linear range of excretion kinetics ; there were no corresponding neurohistopathological findings; there were no indications of neurotoxicity in the rest of the toxicity database; and the endpoints selected for risk assessment are protective of

these adverse effects.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young An imal

Rat and rabbit fetuses did not demonstrate an increased sensitivity to in utero fluridone exposure. Developmental toxicity was either at doses concurrent with or higher than maternal toxicity. Suggestive evidence of susceptibility was observed in the young animals from the F 2 generation (reduced body weight gain during lactation period and body weight on lactation day 21) in the reproductive study . H owever, body weight of the F 2 offspring returned to control levels after the lactation period ; and no e vidence of susceptibility was observed in the F 1 or F 3 offspring. The POD selected to assess risk for chronic dietary and residential exposure is protective of the suggestive susceptibility in young animals.

4.4.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the exposure database. The dietary exposure estimates are unrefined and reflect primarily tolerance

- level residue in food, 100% crop treated (CT), and

upper

- bound drinking water estimates based on modeling. These assumptions and refinements are detailed in the Section 5.4.1. Additionally, HED does not believe that non

- occupational exposure estimates are underestimated. The assumptions are detailed in Section 6.0.

4.5 Toxicity Endpoint and Point of D epa rture Selections

The full suite of submitted toxicity studies used to select endpoints and PODs for each exposure scenario are presented in Appendix A.2. An acute dietary POD was established for the general population and the previous acute dietary POD fo r the female 13

- 49 subpopulation was re

evaluated; otherwise, no updates were made to endpoints from the most recent risk assessment (Drew, 2012, D399892).

4.5.1 Dose

- Response Assessment

The acute reference dose (aRfD) for the general population was set at 1.25 mg/kg/day based on endpoints from the ACN. The NOAEL for the study was 125 mg/kg/day, based on decreased ambulatory counts and the prevalence of FOB anomalies at 650 mg/kg/day. Adverse effects following acute exposure were only seen at relatively h igh doses (>650 mg/kg/day) that are not anticipated based on current and proposed use patterns; however an endpoint was still selected toFluridone Human Health Risk Assessment DP No. 423464

Page 19 of 83 be protective of the observed effects. Uncertainty factors for interspecies variation (10x) and intraspecies variation (10x) were applied to the NOAEL to calculate the aRfD. The acute population adjusted dose (aPAD) was identical to the aRfD, because the FQPA SF was reduced

to 1x. In the previous risk assessment, abortions on gestation days 20

- 25 were selected as the

end point for the female 13

- 49 acute dietary assessment. However, this endpoint was re

- evaluated as part of registration review and determined to not be an acute effect, because the abortions occurred late in the gestation period and were likely the result of multiple doses over the course of the exposure period. None of the acute effects observed in the guideline studies were specific to child bearing females. Consequently, the female 13

- 49 subpopulation was assessed with the general population.

The chronic reference dose (cRfD) was set at 0.15 mg/kg/day based on endpoints from the 2

- year carcinogenicity study in mouse. The NOAEL for the study was 15 mg/kg/day based on increased alkaline phosphatase activity and increased incidence of hepatocellular hyperplas ia at 50 mg/kg/day. Uncertainty factors for interspecies variation (10x) and intraspecies variation (10x) were applied to the NOAEL to calculate the cRfD. The chronic population adjusted dose (cPAD) was identical to the cRfD, because the FQPA SF was reduce d to 1x. A slightly lower NOAEL (8 mg/kg/day) was noted in the rat combined chronic toxicity/carcinogenicity study; however, this

fact was considered to be due to dose

- selection (i.e. 15 mg/kg/day was not tested in this rat study) ; the LOAELs were similar

. The NOAEL in the mouse study is protective of adverse findings noted in the rat combined chronic toxicity/carcinogenicity study, as well as the offspring

effects in the rat 3

- generation reproduction study. The selected NOAEL is also protective of

effects noted in the chronic dog study.

The 2

- year mouse study was used to set residential POD s for short

- and intermediate

- term incidental oral, dermal and inhalation exposure and occupational POD s for short

- and

intermediate

- term dermal and inhalation exposure

. The main effects in this study are detailed in the previous paragraph.

The mouse chronic endpoint was appropriate for short

- and intermediate

- term fluridone exposures, because : (i) mice were the most sensitive species in subchronic exposures; (ii)

fluri done is rapidly metabolized and eliminated from the body at low doses (≤10 mg/kg) in acute and repeat dosing metabolism studies with a similar pattern of excretion (amount in feces and urine and rate of excretion); and (iii) no progression of toxicity was evident when comparing the mouse subchronic toxicity study to the chronic toxicity study. Progression of toxicity was observed in rats; however, rat sensitivity was either less than (subchronic exposure) or similar (chronic exposure) to mice. The POD from the 2

- year mouse study was, therefore, both protective of the effects observed in rats and representative of short

- and intermediate

- term exposure durations.

The guideline dermal study was not used to set endpoints for the dermal assessment, because the study did not address concerns for the possible sensitivity in the young observed in the

3

- generation reproduction study. The systemic NOAEL from the dermal study is 384 mg/kg/day, but offspring toxicity is apparent at 112 mg/kg/day. The NOAEL from the 2

- year mouse cancer study is 38.5 mg/kg/day, after accounting for route

- to

- route extrapolation (DAF=39%), which is protective of the offspring effects. The mouse oral endpoints were used for the inhalationFluridone Human Health Risk Assessment DP No. 423464

Page 20 of 83 assessment, because a route

- sp ecific inhalation study was not available

. Inhalation exposure was assumed to be equivalent to oral exposure.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. Exposures via the oral, der mal and inhalation routes can be combined for short

- and intermediate

- term
assessments because PODs for these rout es were all based on liver effects observed in the 2 year mouse carcinogenicity study (increased alkaline phosphatase activity and incidence of hepatocellular hyperplasia).

4.5.3 Cancer Classification and Risk Assessment Recommendation

Fluri d o ne did no t demonstrate mutagenic behavior either in vitro or in vivo nor did exposure result in an increased incidence of tumors. The HED Cancer Peer Review Committee (TXR 0007726, July 15 and October 7, 1985) concluded that fluridone should be classified as “not

l ikely” to be a human carcinogen and a subsequent quantitative cancer risk assessment is not required

.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Fluridone for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,
Level of
Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population) NOAEL =

125 mg/kg/day UF A =10x

UF H =10x

FQPA SF = 1X a RfD =

aPAD = 1.25 mg/kg/day Acute Neurotoxicity

- Rat

LOAEL = 650 mg/kg/day based decreased ambulatory counts and the prevalence of FOB anomalies in males

and females

Chronic Dietary (All Populations) NOAEL=

15 mg/kg/day UF A =10x

UF H =10x

FQPA SF= 1 x c RfD =

cPAD = 0.15 mg/kg/day 2

- year cancer study

– Mouse

LOAEL = 50 mg/kg/day based on increased alkaline phosphatase activity

and increased incidence of hepatocellular hyperplasia

Incide ntal

Oral Short

and

Intermediate

Term NOAEL =

15 mg/kg/day UF A =10x

UF H =10x

FQPA SF=1x MOE = 1 00 2

- year cancer study

– Mouse

(Same as above)Fluridone Human Health Risk Assessment DP No. 423464

Page 21 of 83 Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Fluridone for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of
Concern for

Risk
Assessment Study and Toxicological Effects

Dermal Short

and

Intermediate

Term NOAEL =

15 mg/kg/day UF A =10x

UF H =10x
dermal absorption
factor = 39% MOE = 1 00 2

- year cancer study

– Mouse

(Same as above)

Dermal Long

Term This endpoint is not applicable because use patterns preclude long term exposure

Inhalation

Short

- and

Intermediate

term NOAEL =

15 mg/kg/day UF A =10x

UF H =10x MOE = 100 2

- year cancer study

– Mouse (Same as above)

Inhalation Long

- Term This endpoint is not applicable because use patterns preclude long term exposure

Cancer (oral ) Fluridone is classified as “not likely” to be a human carcinogen. Quantitative cancer risk assessment is not required (TXR 007726)

. Point of Departure ( POD ) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessme nt. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluridone for Use in Occupational

Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short

and

Intermediate

Term NOAEL =

15 mg/kg/day UF A =10x

UF H =10x MOE = 1 00 2

- year cancer study

– Mouse

(Same as above)

Dermal Long

Term This endpoint is not applicable because use patterns preclude long term exposure

Inhalation

Short

- and

Intermediate

term NOAEL =

15 mg/kg/day UF A =10x

UF H =10x MOE = 100 2

- year cancer study

– Mouse (Same as above)Fluridone Human Health Risk Assessment DP No. 423464

Page 22 of 83 Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluridone for Use in Occupational

Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Inhalation Long

- Term This endpoint is not applicable because use patterns preclude long term exposure

Cancer ( dermal, inhalation) Fluridone is classified as “not likely” to be a human carcinogen. Quantitative cancer risk assessment is not required (TXR 007726)

.

Point of Departure ( POD ) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessme nt. UF DB = to account for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to asses s potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. The se studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss,

and sex ratios in o ffspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its preliminary re

- registration decision for fluridone , EPA revi ewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However , as required by FFDCA section 408(p), fluridone is subject to the endocrine screening part of the Endocrine Disrupto r Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical subst ance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP w here EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.Fluridone Human Health Risk Assessment DP No. 423464

Page 23 of 83 Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide a ctive ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for Registration Review and chemicals found in water

. Neither of these lists

should b e construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

website 2

.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Fluridone irrigated crop metabolism studies were conducted on grapefruit, corn, soybeans, lettuce, and alf alfa

. In addition, soil applications were conducted with corn and alfalfa. Greater than 73% of the residue in all crops was identified as the parent compound, fluridone. The risk assessment team has reviewed the applicable studies and has determined that if finite residues are present, fluridone is the most likely species present.

Livestock metabolism studies have been conducted with cattle, swine, and chickens. All studies have shown considerable metabolism of the parent compound with subsequent incorp oration into

the livestock tissues. Fluridone and its 4

- hydroxy metabolite were found in cattle and swine liver at levels less than 4% each of the total radioactive residue (TRR) for cattle and 0.5% each for swine. No attempt was made to identify the TRR in poultry, due to low levels. Given the relatively low dietary burden of fluridone, and the extensive metabolism of fluridone and the low residues expected in edible commodities, the risk assessment team has concluded that the residue

of concern for ri sk assessment and tolerance

- setting purposes is the parent, fluridone

.

5.1.2 Summary of Environmental Degradation

Fluridone is relatively non

- volatile, and moderately mobile in soil. The compound is relatively persistent in soil, with a 213

- day half

- life in moist soil and a 117

- day half

- life in flooded soil. Fluridone’s degradation under anaerobic conditions is uncertain due to lack of acceptable data.

Fluridone did not photolyze in soil in one system and acceptable data are not available to describe photolysis in water.

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.

2 http://www.epa.gov/endo/Fluridone Human Health Risk Assessment DP No. 423464

Page 24 of 83 Fluridone does not abiotically hydrolyze in water. It bioconcentrates in fish only to 44x, and its depuration rate is unknown. Acceptable aquatic metabolism data are not available.

Sorption of fluridone to soil correlates with soil organic carbon content (FAO soil mobility classification of moderately mobile; FAO, 2014). With moderate mobility in soil and little to no degradation in sub

- surface soils, fluridone m ay pose a ground water concern.

Important means of transport off of agricultural fields following application will include spray drift, runoff of residues, and leaching. Fluridone dissipated in the field with half

- lives in soil ranging from 38 days to >1 5 months, and half

- lives in water bodies ranging from 5 to 60 days, all based on studies in review.

5.1.3 Comparison of Metabolic Pathways

In plant metabolism studies, g reater than 73% of the residue in all crops was identified as the parent compound, fl uridone. All livestock metabolism studies have shown considerable metabolism of the parent compound with subsequent incorporation into the livestock tissues.

In a metabolism study in rats, fluridone was rapidly and almost completely absorbed into the

sy stemic circulation and eliminated in both the male and female rats within 3 days. The total radioactivity recovered within 3 days after dosing in the uri ne and feces were 78

- 90% and

87

- 97% of administered dose in males and females, respectively. The majo rity (approximately 70%) of the radioactivity was eliminated via feces. No tissue accumulation was observed. The major components in the feces were fluridone and fluridone metabolites produced primarily by ring hydroxylation and N

- demethylation.

5.1.4 R esidues of Concern Summary and Rationale

A summary of the fluridone metabolites and degradates included in the risk assessment and tolerance expression is included in Table 5.1. 4. No major plant metabolites were found in the irrigated crop study, so only the parent compound is included. Extensive metabolism of the low total residues were found in the ruminant, poultry, and swine metabolism studies, so no major degradates were i dentified. 4

- hydroxyfluridone is the major degradate in fish and is assumed to have approximately equivalent toxicity to the parent , so both are included in the risk assessment and tolerance expression. Benzoic acid and its 3

- trifluroromethyl benzoic aci d are aqueous photolysis products found in laboratory studies conducted with lake water. Although these compounds would not have toxicity profile s similar to the parent considering their molecular

structures , there is not a concern for adverse health effects at the levels found as a result of fluridone applications.

A nother aqueous photoproduct found in laboratory studies, N

- methylformamide ( NMF ) , is more toxic than the parent compound and requires a separa te assessment (Dole, 2004, D306456). According to the Environmental Fate and Effects Division (EFED), NMF remains a residue of concern unless acceptable aqueous photolysis data are submitted (Orrick; 2015, D423846). An assessment for NMF is provided in Ap pendix E.Fluridone Human Health Risk Assessment DP No. 423464

Page 25 of 83 Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Fluridone Fluridone

Rotational Crop Fluridone Fluridone

Livestock Ruminant Fluridone Fluridone

Poultry Fluridone Fluridone

Fish Fluridone

4

- hydroxyfluridone Fluridone

4

- hydroxyfluridone

Drinking Water Fluridone, N

methylformamide (NMF) a Not Applicable

a. An assessment for NMF is provided in Appendix E.

5 .2 Food Residue Profile

There is adequate residue data for risk assessment and tolerance assessment. An irrigated crop study was used to set the current inadvertent tolerances of fluridone

, which are li sted in the

40CFR 180.420. R esidue data on irrigated crops involved studies on two crops from each crop grouping. Residues were below the limit of detection (<0.05 ppm) for most crops. It was determined that the appropriate tolerance level would be 0.1 pp m for all crops for which there were no direct uses, except for animal feed non

- grass group 18 and grass forage; a tolerance of 0.15 ppm would be appropriate for those livestock feed items.

Adequate storage stability data was submitted.

The residues found in the present metabolism and distribution on representative crops studies represent the maximum levels that are likely to be encountered through direct irrigation from water treated with fluridone from the currently registered aquatic u se, and also for crops that may be grown in rotation with treated cotton. The confined rotational crop studies indicate no uptake of fluridone from soil containing residues that would be expected within one month of application to bare soil in root and tub er vegetables and leafy vegetables (as levels were constant in the soil from the time of application to the end of the one year aging period), and in cereals after a five month aging period.

Wheat and soybean rotational crops (planted following harvest of cottonseed) showed no

detectable resid ues after plantback intervals of 5 and 12 months, respectively . Total radioactive

residues w ere very low, 0.003 and 0.002 ppm in beets and lettuce, respectively, grown in bare

soil treated at 0.4 lb ai/A following a 1 0 month plantback interval

. The proposed plant back

interval on the label is adequate

, which ranges from 8 to 18 months for various crops.

No detectable residues were found in meat, milk, poultry, and eggs (MMPE). The current tolerances for MMPE are adequate. Cotton gin byproducts do not have an impact on the livestock dietary burden.Fluridone Human Health Risk Assessment DP No. 423464

Page 26 of 83 No residue data were submitted with the Section 3 reques t for use on cotton . Several literature and unpublished study citations were provided by the petitioner . The residues found in the cotton

studies were non

- detectable in all samples, including those treated at exaggerated rates. This

issue was addressed in HED’s Chemistry Science Advisory Council (ChemSAC), and it was agreed upon that no additional field trials were needed. The limit of detection (LOD) was determined to be 0.01 ppm for cotton. The conclusions of select unpublished studies were briefly

summa rized and indicated that residues of fluridone on cotton would not be expected to exceed the tolerance of 0.1 ppm.

Given the absence of fluridone residues in cottonseed and w hole cotton plants from geographically appropriate field trials conducted at exa ggerated rates (1.3X

- 6.7X compared to the proposed rate of 0.3 lb ai/A), it can be concluded that residues of fluridone from the proposed S3 use would not exceed the current tolerance level of 0.1 ppm for cottonseed, undelinted.

Based on nondetectable r esidues in the RAC in the exaggerated rate studies, residues would not be expected in cotton processed commodities and separate tolerances would not be needed.

In the absence of cotton gin byproducts magnitude of the residue data, the TRR data for whole

p lants provided in the metabolism study should be used to determine the tolerance for cotton gin byproducts. HED has recommended that a tolerance for fluridone on cotton gin byproducts also be established at 0.1 ppm.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED ( Orrick,

2015

, D423846 ) and incorporated directly into this dietary assessment as point estimates

. The maximum screening

- level acute and chronic estimated drinking water concentrati ons ( EDWCs : 34 and 32 μg/L, respectively) are based on the proposed use of fluridone on cotton at 0.3 lbs a.i./acre per year. Water residues in Table 5.3 were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” The most conservative values, based on ground water modeling (Tier I: PRZM

- GW), were used in the acute (0.034 ppm) and the chronic (0.032 ppm) assessments.

Table 5.3

. Summary of Estimated Surface Water and Groundwater Concentrations for Fluridone

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 24 34

Chronic (non

- cancer) 21 32

a From the T ier I FIRST.

b From the PRZM

- GW model.
Fluridone: Drinking Water Exposure Assessment for Proposed New use on Cotton” (Orrick, 2015 , D 423846 )Fluridone Human Health Risk Assessment DP No. 423464

Page 27 of 83 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Fluridone is not applied directly to crops or livestock, but treated water may be used to irrigate food and feed crops or fed to livestock. Tolerances have been established in 40 CFR §180.420 for crop groups. The proposed Section 3 use on cotton is a dire ct soil application; however, the tolerance is the same as for fluridone use on cotton as an irrigated crop. Tolerance values were used in the acute and chronic dietary exposure assessments with no refinements for percent crop treated. The default proces sing factors in DEEM

- FCID, Version 3.16 were also used. The drinking water residues for fluridone used in the dietary risk assessment were provided by EFED and incorporated directly into this dietary assessment as point estimates (see Section 5.3)

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

No refinements were done for crop treated; 100% crop treated was used for fluridone in the

assessment.

5.4.3 Acute Dietary Risk Assessment

The acute dietary (food and drinking water) assessment was u nrefined. 100% crop treated, established tolerance residues, and default processing factors were used for this assessment. For acute assessments, HED is concerned when dietary risk exceeds 100% of the PAD. T he most highly exposed sub

- population was childr en age d 1

- 2, with a risk estimate of 1.3% of the a PAD (at the 95 th percentile of exposure)

. These risk estimates are all well below 100% of the PAD and

are not of concern. The DEEM

- FCID  analyses estimate the dietary exposure of the U.S. population and various population subgroups. The results are reported in Table 5.4.6 for

fluridone for the general U .S. Population, all infants (<1 year old), children 1

- 2, children 3

- 5,

children 6

- 12, y outh 13

- 19, females 13

- 49, adults 20

- 49, and adults 50+ years.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) assessmen t was unrefined. 100% crop treated, established tolerance residues, and default processing facto rs were used for this assessment. For chronic assessments, HED is concerned when dietary risk exceeds 100% of the PAD. T he most highly exposed sub

- population was children age d 1

- 2, with a risk estimate of 5.5 % of the cPAD.

These risk estimates are all well below 100% of the PAD and are not of concern. The DEEM

FCID  analyses estimate the dietary exposure of the U.S. population and various population subgroups. The results reported in Table 5.4.6 are for the general U.S. Population, all infants (<1

yea r old), children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19, females 13

- 49, adults 20

- 49, and adults 50+ years.Fluridone Human Health Risk Assessment DP No. 423464

Page 28 of 83 5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not conducted, as fluridone is classified as “not likely to be

carci nogenic”.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary Food and Drinking Water Exposure and Risk for Fluridone

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population 0.006443 <1 0.002583 1.7
All Infants (<1 year old) 0.011772 <1 0.004922 3.3

Children 1

- 2 years old 0.015597 1.3* 0.008312 5.5*

Children 3

- 5 years old 0.011639 <1 0.006077 4.1

Children 6

- 12 years old 0.007305 <1 0.003568 2.4

Youth 13

- 19 years old 0.004442 <1 0.002129 1.4

Adults 20

- 49 years old 0.004236 <1 0.002098 1.4
Adults 50+ years old 0.003918 <1 0.001975 1.3

Females 13

- 50 years old 0.004157 <1 0.002042 1.4
*The highest exposed population subgroup

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential uses

that have been reassessed in this document for Registration Review. The registered aquatic use s have been assessed according to HED’s November 2015 Draft Aquatic Use SOP

. Residential

handler and post

- application exposures are expected for fluridone. The revision of residential exposures will impact the human healt h aggregate risk assessment for f luridone

.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that

exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED

, as homeowners are assumed to complete all elements of an application without use of any protective equipment.

The ready

- to

- use (RTU) aquatic products registered for fluridone state that “unless the pond is privately owned by the applicator, prior to application, consult with appropriate state or local

water authorities.” Therefore , it is assumed that this type of product can be applied by the homeowner to their privately owned pond. The quantitative exposure/risk assessment developed

for residential handlers is based on the following scenario :

• Ready

- to

- use (RTU) aquatic application sFluridone Human Health Risk Assessment DP No. 423464

Page 29 of 83 Residential Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below.

Application Rate: The maximum rate for residential use from Table 4.1.2 was used; 0.12 lb

ai/a cre

- foot = 0.00000275 lb ai/ft 3

.

Unit Exposures and Area Treated or Amount Handled : Unit exposure values to represent a homeowner pouring a RTU formulation have been adjusted

from the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 3 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 4

. The occupational unit exposure (representing long

- sleeved shirt, long pants, and no gl oves) has been adjusted to represent a homeowner wearing a short

- sleeved shirt and shorts. Es timates for area treated or amount

handled were taken from HED’s Draft November 2015 Aquatic Use SOP.

Exposure Duration: Residential handler exposure is expected to be short

- term in duration.

Intermediate

- term exposures are not likely because of the intermittent nature of applications by

homeowners.

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations The algorithms used to estimate exposu re and dose for residential handlers can be found in Appendix A and/or the 2012 Residential SOPs 5 and/or the draft November 2015 Aquatic Use

SOP.

Combining Exposures/Risk Estimates:

Dermal and inhalation risk estimate s were combined in this assessment, si nce the toxicological effects for these exposure routes were the same . Dermal and inhalation risk estimate s were combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) ÷ Combined D ermal + I nhalation dose ( mg/kg/day)

Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates

Residential handler combined dermal and inhalation MOEs range from 1,800 to 1,400 ,000. Since the MOEs are greater than the LOC of 100, there are no risk estimates of concern for

residential handlers.

3 Available: http://www2.epa.gov/sites/production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf

4 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

exposure

- data

5 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

residential

- pesticideFluridone Human Health Risk Assessment DP No. 423464

Page 30 of 83 Table 6 .1.1. Residential Handler Non

- C ancer Exposure and Risk Estimates for Fluridone.

Exposure Scenario Level of

Concern Dermal Unit Exposure (mg/lb ai) 1 Inhalation Unit Exposure

(mg/lb ai) 1 Maximum Application

Rate 2 Area Treated or

Amount Handled Daily 3 Dermal Inhalation Combined

Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE
(LOC = 100) 8

Mixer/Loader/Applicator

Ready

- to

- use

– Open Pour

to Recreational Ponds 100 0.232 0.219 0.12 lb ai/acre

foot 2.5 acres, 7 foot depth 0.00 24 6,300 0.0057 2,600 1,800

Ready

- to

- use

– Open Pour

to Ornamental Ponds 100 0.232 0.219 0.00000275 lb

ai/ft3 500 ft 2 , 2 foot depth 0.00000 31 4,800 ,000 0.0000075 2,000,000 1,4 00,000

1 Unit exposure values based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015) a djusted for difference in clothing (short

- sleeved shirt and short

pants vs long

- sleeved shirt and long pants). 2. Based on registered labels.

3 Based on HED’s Draft November 2015 Aquatic SOP.

4 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre

- ft or lb ai/ft3) × Area Treated or Amount Handled (A

- ft/day or ft3/day) × Dermal Absorption Factor (39%) ÷ Body

Weight (80 kg).

5 Dermal MOE = Dermal NOAEL (15 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre

- ft or lb ai/ft3) × Area Treated or Amount Handled (A

- ft/day or ft3/day) ÷ Body Weight (80 kg).

7 Inhalation MOE = Inhalation NOAEL (15 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (15 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).Fluridone Human Health Risk Assessment DP No. 423464

Page 31 of 83 6.2 Residential Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with fluridone. The recreati onal swimmer has the potential for exposure to fluridone in treated water

. The quantitative exposure/risk

assessment for residential post

- application exposures is based on the following scenarios:

• Adults and children (3 to <6 years old) swimming in tre ated water (dermal , inhalation and incidental ingestion)

Residential Post

- A pplication Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each ass umption and factor is detailed in the Draft 2015 Aquatic Use SOP.

Application Rate: As was done in the previous assessments, the maximum label rate of 150 ppb (0.15 mg/L) was used to assess aquatic exposure of fluridone.

Exposure Duration: Residential exposure is expected to be short

- term in duration.

Residential Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential post

- application exposure and dose can be found in Appendix A and/or the Draft November 2015 Aquatic Use SOP.

Combining Exposure and Risk Estimates Since dermal, inhalation and incidental oral exposure routes share a common toxicological endpoint, exposure estimates have been combined for those routes.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates For fluridone, the combined MOE for adults swimmers is 52,000 and for child swimmers is 12,000; therefore, there are no risk estimates of concern (LOC = 100).

Table 6 .2.1. Residential Post

- applica tion Non

- cancer Exposure and Risk Estimates for Fluridone.

Lifestage Post

- application Exposure

Scenario Application

Rate 1 Dose (mg/kg/day) 2 MOEs 3 Combined Routes (X indicates Combined) Combined MOEs

Use Site Route of Exposure

Adult

Aquatic Dermal

150 ppb 0.00028 54 ,000 X

52 ,000 Inhalation 4.05 E

- 8 370 ,000,000 X

Incidental Ingestion 9.4E

- 6 1,600,000 X

Child (3 to <6 years) Dermal 0. 00 114 13 ,000 X

12 ,000 Inhalation 2.8 E

- 7 54 ,000,000 X

Incidental Ingestion 9.87E

- 5 150,000 X

1 Based on registered labels.

2 Dose (mg/kg/day) equations :

• Inhalation Dose (mg/kg/day) = [Concentration in water (0.15 mg/L) * Dimensionless Henry’s law constant ( 3.38E

- 07 ) * CF (1000

L/m 3 ) * IR (0.64 m 3 /hr for adults and 0.32 m 3 /hr for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (80 kg for adults and 19 kg for children).

• Dermal dose (mg/kg/day) = [Concentration in water (0.15 mg/L) * Permeability constant ( 0.0763 ) * Surface area (19,500 cm 2 forFluridone Human Health Risk Assessment DP No. 423464

Page 32 of 83 adults and 7,600 cm 2 for child ren) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (80 kg for adults and 19 kg for children).

• Incidental ingestion dose (mg/kg/day) = [Concentration in water (0.15 mg/L) * Ingestion rate (0.05 L/hr) * Exposure time (0.1 hr for

adults a nd 0.25 hr for children)] / BW (80 kg for adults and 19 kg for children).

3 MOE = POD (15 mg/kg/day) ÷ Dose (mg/kg/day).

4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6 .3.1 reflects the residential risk estimates that are recommended for use in the aggregate

assessment for fluridone

.

• The recommended residential exposure for use in the adult aggregate assessment reflects

derm al and inhalation exposure from applications via pouring to recreational ponds

.

• The recommended residential exposure for use in the child (3 to <6 years old) aggregate assessment reflects dermal, inhalation, and incidental oral exposures from post

applicat ion exposure to aquatic applications.

Table 6

. 3.1. Recommendations for the Resident ial Exposures for the Fluridone Aggregate Assessment.

Lifestage Exposure
Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Handler

– RTU 0.0024 0.0057 N/A 0.0081 6,300 2,600 N/A 1,800

Child (3 to < 6 years old) Swimming 0.00114 2.8E

- 7 9.9E

- 5 0.0012 13,000 54,000,000 150,000 12,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed . Total = dermal + inhalation + incidental oral (where applicable)

. 2 MOE = the MOEs associated with the highest residential doses . Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MOE), where applicable

.

6.4 Residential Bystander Post

- A pplication Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review , the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for

fluridone.

6.5 Spray Drift

Off

- target movement of pesticides can occur via many types of path ways, and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up

off

- target and can lead to exposures to those people it may directly contact. They can alsoFluridone Human Health Risk Assessment DP No. 423464

Page 33 of 83 deposit on surfaces where contact with residues can eventually lead to indirect exposures ( e.g. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50

- feet wide lawns

coup led with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 6 Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed he re are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who have contact with

turf where residue s are assumed to have deposited via spray drift, thus resulting in an indirect exposure, are the focus of this analysis analogous to how exposures to turf products are

considered in risk assessment.

In order to evaluate the drift potential and associate d risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to

address drift from t he agricultural applications of fluridone

. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift (v2.1.1) model a nd the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy . Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening approach was developed based on the use of the AgDrift model in situations where specific label guidance that defines application parameters is not available. 7 AgDrift is appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorpora ted into the model and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for

com mon application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of ecological risk assessments and in the process used to develop drinking water concentrations used for risk assessment. In all cases, each scenario is to be evaluated, unless it is not plausible based on the anticipated use pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed). Section 6

. 5 .1 provides the screening level drift

- related risk estimates.

6 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

7 http://www.agdrift.com/Fluridone Human Health Risk Assessment DP No. 423464

Page 34 of 83 6.5 .1 Risk Estimates From Lawn Deposition Adjacent to Applications

Fluridone is a systemic herbicide, meaning its herbicidal mode of action require s it to be

absorbed and translocated in the weeds. It is not a contact herbicide

, and thus the application method is not as a broadcast application meant to cover the surface area of the weeds. For the aquatic uses, i t is applied in a directed manner, usually using a hose, wand or meter, as a surf ace or subsurface application to water in order to maintain a specified herbicide concentration in the water body to control aquatic weeds systemically. The large/coarse droplet size and directed spray methods greatly reduce the spray drift potential for aquatic applications. As the application methods are not conducive to spray drift as described and assessed as part of the spray drift policy, a quantitative spray drift assessment is not required for the aquatic uses of the

herbicide.

The spray drift risk estimates for the proposed use on cotton are based on an estimated deposited residue concentration, as a result of the screening level agricultural application scenarios. Fluridone is proposed for use on pre

- emergent cotton and can be applied via gro undboom. Aerial application is prohibited. The spray drift assessment was completed assuming the highest proposed single application rate to cotton of 0.3 lb ai/A. The recommended drift scenario screening level options are:

• Groundboom applications are based on the AgDrift option for high boom height and using very fine to fine spray type using the 90 th percentile results.

The applicable Level of Concern is 100, so MOEs < 100 would be of concern. Exposures were

considered for 50 feet wide lawns where the nearest side of the property was directly adjoining the treated field (at field edge). Results are presented in Table 6.5.1 ; no risk estimates of concern were identified at field edge.

Table 6.5 .1 Adult and Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for
Fluridone

.

Population

and Exposure

Route Application

Method Spray Type/ Nozzle Configuration Appl. Rate (lb ai/A) TTR (μg/cm 2 ) a MOE At Field Edge

Cotton

Adults

– Dermal Groundboom High Boom Very fine to Fine

0.3 0.033 1,800

Children (1 to

<2 years)

– Combined

Dermal and

Hand

- to

mouth Groundboom High Boom Very fine to Fine 880

a. TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.1 and D = 0.10 per dayFluridone Human Health Risk Assessment DP No. 423464

Page 35 of 83 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures fro m relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and

duration of exposure.

7.1 Acute Aggregate Risk

The acute aggregate risk is equivalent to the acute dietary risk estimates. The acute dietary exposure estimates for fluridone (food and drinking water) ar e not of concern to HED (<100%

a PAD) for the general U.S. population an d all population subgroups

.

7.2 Short

- Term Aggregate Risk

Short

- term aggregate risk assessments for fluridone are neces sary since there is potential for

residential exposure to fluridone from the aquatic uses. For the short

- term aggregate risk assessment, potential residential exposures were combined with chronic dietary exposures. See

Table 6.3 .1 for more information on the residential risk estimates that are recommended for use in the aggregate assessment for fluridone

. The short

- term reside ntial exposure estimates were aggregated with the chronic dietary exposure to provide a worst

- case estimate of short

- term aggregate risk for adults and children. The short

- term aggregate MOEs for adults and children are greater than the LOC of 100 for flu ridone and are therefore not of concern.

Table 7.2 .1 Short

- Term Aggregate Risk Calculations for Fluridone

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day 3 Residential Exposure mg/kg/ day 4 Total Exposure mg/kg/ day 5 Aggregate MOE (food, water, and residential) 6

Adult 15 100 0.15 0.002098 0.0081 0.0 102 1,500

Child 15 100 0.15 0.008312 0.0012 0. 009512 1, 6 00

1 LOC based on the standard inter

- and intra

- species uncertainty factors totaling 100

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Average food and water exposure from chronic dietary exposure for adults 20

- 49 yrs and children 1

- 2 yrs old (see Table 5.4.6.1).

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure] , where applicable

. 5 Total Exposure = Avg Food & Water Exposure + Residential Exposure

6 Agg regate MOE = [NOAEL (15 mg/kg/day) / ( Total Exposure, mg/kg/day )]

7.3 Intermediate

- Term Aggregate Risk

Intermediate

- term residential exposures are not likely because of the intermittent residential exposure to fluridone ; t herefore , an intermediate

- term aggregate risk assessment is not required.Fluridone Human Health Risk Assessment DP No. 423464

Page 36 of 83 7.4 Chronic Aggregate Risk

There are no chronic residential exposure scenarios; therefore, the chronic aggregate risk is equival ent to the chronic dietary risk estimate . The chronic dietary (food and drinking water) exposure estimates for fluridone are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups

.

7.5 Cancer Aggregate Risk

Fluridone is classified as “not lik ely” to be a human carcinogen. A q uantitative cancer risk assessment is not required

.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to fluridone and any other substances and fluridone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not

assume d that fluridone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy sta tements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or t asks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handl er can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the registered and proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

Proposed use on cotton:

• Mix/load liquid for groundboom application to pre

- emergent cotton

• Applying spray by groundboom application to pre

- emergent cottonFluridone Human Health Risk Assessment DP No. 423464

Page 37 of 83 Registered aquatic uses:

• Mix/load liquid for aerial/boom application or direct metering to lakes/canals

• Mix/load WDG/granule for aerial/boom application to lakes/canals

• Applying spray by aerial/boom application to aquatic area

• Applying granule by aerial/boom application to aquatic area

• Mixing/loading/applying with handheld equipment to aquatic areas (lakes/canals)

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposur e factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate : Application rates are provided in Table s 3.3.1 and 3.3.2

.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, or other registrant

- submitted occupatio nal exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit e xposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 8 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Ag ency website 9

.

Area Treated or Amount Handled: For proposed cotton use: 200 acres for groundboom application to high

- acreage crop (based on ExpoSAC Policy 9.1).

For existing aquatic use : area treated assumption (30 acres) is based on information from t he Army Corp of Engineers [for more details, please see the occupational aquatic assessment in the endothall reregistration eligibility decision ( Tadayon , 2005, D319373 ) and the 2,4

- D RED ( Dole

, 2005 , D316596 ) . The depth of 7 feet is assumed to be consistent with the EFED farm pond

model. For application to aquatic sites with handheld equipment, it is assume the area treated is

5 acres of surface area and a depth of 1 foo t. For static canals, the area treated is assumed to be a canal 1 mile long a nd 20 ft wide (2.5 acres). For assessing flowing water, it is assumed that the upper end of the flow rate is 200 cubic feet/second (endothall RED, Tadayon, 2005, D319373 ). This is equivalent to approximately 400 acre

- feet treated.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the

pes ticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for

more than a one

- month time frame; however, there may be a large agribusiness and/or

8 Available: http://www2.epa.gov/sites/production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf

9 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

exposure

- dataFluridone Human Health Risk Assessment DP No. 423464

Page 38 of 83 commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For fluridone, based on the proposed use, short

- and intermediate

- term exposures are expected.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consis ting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels

of PPE as necessary (e.g., gloves, respirator, etc). The proposed product label for the pre

emergent cotton use di rects applicators and other handlers to wear long sleeved shirt, long pants,

chemical

- resistant gloves, shoes plus socks and protective eyewear. The registered product

labels for the aquatic uses do not require any PPE.

Occupational Handler Non

- Cancer Exposure and Risk Estimate Equations The algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Appendix A of the ORE memo ( Gavelek , 2015, D4 31020 )

.

Combining Exposures/Risk Estimates:

Dermal and inhalation exposure estimates were combined in this assessment, since the toxicological effects for these exposure routes were the same. Dermal and inhalation exposure estimates were combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) ÷ Combined dermal + inhalation dose (mg/kg/day)

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates

Proposed Cotton Use : There are no risk estimates of concern for the proposed cotton use (i.e., all MOEs ≥ LOC of 100; see Table 9.1.1). Occupational handler combined dermal and

inhalation MOEs range from 230 to 640 with baseline clothing ( long sleeved shirt, long pants

, shoes plus socks, no gloves, and no respirator for all scenarios except aerial applicator where engineering controls were used). The proposed product label for the pre

- emergent cotton use directs applicators and other handlers to wear long sleeved shirt, long pants, chemical

- resistant gloves, shoes plus socks and protective eyewear.

Registered Aq uatic Uses: There are risk estimates of concern for some of the registered aquatic use scenarios (see Table 9.1.2). Occupational handler combined dermal and inhalation MOEs range from 6.1 to 18,000 with baseline clothing (single layer clothing, shoes plu s socks, no gloves, and no respirator for all scenarios

, except aerial applicator where engineering controls were used)

. The registered product labels for aquatic uses do not require any PPE. The scenario of mixing/loading/applying product with handwand sprayer to aquatic sites was not of concern with the addition of gloves. The scenario of mixing/loading/applying product with backpack sprayer to aquatic sites was not of concern with the addition of double layer clothing and gloves.

HED has no data to a ssess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls,Fluridone Human Health Risk Assessment DP No. 423464

Page 39 of 83 pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.Fluridone Human Health Risk Assessment DP No. 423464

Page 40 of 83 Table 9 .1.1. Occupational Handler Non

- Cancer Ex posure and Risk Estimates for the Proposed Uses of Fluridone on Cotton

.

Exposure Scenario Crop or Target Level of

Concern Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit Exposure (μg/lb ai) 1 Maximum Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Combined

Mitigation

Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE
(LOC = 100) 8

Mixer/Loader

Mixing/loading liquid for Groundboom Application Cotton 100 SL/No G :

220 No R:

0.219 0.3 lb

ai/acre 200 acres 0.0644 230 0.000164 91,000 230

Applicator

Applying Spray with Groundboom Application Cotton 100 SL/No G:

78.6 No R:

0.34 0.3 lb ai/acre 200 acres 0.023 650 0.000255 59,000 640

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ); Level of mitigation: SL/ No G = Single layer, no gloves.

2 Based on proposed label

. 3 Exposure Science Advisory Council Policy #9.1

. 4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL ( 15 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL ( 15 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL ( 15 mg/kg/day) ÷ Dermal Dose + Inhalation Dose

.

Table 9 .1. 2 . Occupational Handler Non

- Cancer Ex posure and Risk Estimates for the Registered Aquatic Uses of Fluridone

.

Exposure Scenario Crop or Target Level of

Concern Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit Exposure (μg/lb ai) 1 Maximum Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Combined

Mitigation

Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE
(LOC = 100) 8

Mixer/Loader

Mix/Load Liquid for Aerial/Boom Application or Direct Metering Aquatic:

Pond/Lake 100 SL/No G :

220 No R:

0.219

0.4 lb

ai/acre

- foot 30 acres / 7 foot depth 0.0902 170 0.00023 65,000 170

Mix/Load Granular for Aerial/ Boom Application SL/No G:

8.4 No R:

1.7 0.00344 4,400 0.00179 8,400 2,900

Mix/load WDG for Aerial/ Boom application SL/ No G: 227 No R: 8.96 0.0931 160 0.00941 1,600 150Fluridone Human Health Risk Assessment DP No. 423464

Page 41 of 83 Table 9 .1. 2 . Occupational Handler Non

- Cancer Ex posure and Risk Estimates for the Registered Aquatic Uses of Fluridone

.

Exposure Scenario Crop or Target Level of

Concern Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit Exposure (μg/lb ai) 1 Maximum Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Combined

Mitigation

Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE
(LOC = 100) 8

Mixing/loading liquid for direct metering Aquatic: Moving

Water 100 SL/No G :

220 No R:

0.219 40 ppb; 0.11

lb ai/acre

foot 200 CFS =

400 acre

feet/day 0.0472 320 0.000121 120,000 320

Applicator

Applying spray with Aerial Application

Aquatic:

Pond/Lake 100 Eng. Control:

2.08 Eng. Control:

0.0049

0.4 lb

ai/acre

- foot 30 acres /

7 foot depth 0.000853 18,000 0.0000052 2,900,000 18,000

Applying spray with Boat Boom Application SL/No G:

78.6 No R:

0.34 0.032 470 0.000358 42,000 460

Applying granular with

Aerial Application Eng. Control :

1.7 Eng. Control :

1.3 0.000697 22,000 0.00136 11,000 7,300

Applying granular with boat spreader SL/No G:

9.9 No R:

1.2 0.00406 3,700 0.00126 12,000 2,800

Mixer/loader/Applicator

Mixing/loading/applying liquid/WDG with backpack

sprayer

Aquatic:

Pond/Lake 100 SL/No G:

8260 No R:

2.58

0.4 lb

ai/acre

- foot 5 acre / 1 foot depth 0.0804 190 0.0000645 2 3 0 ,000 190

Mixing/loading/applying liquid /WDG with

handwand sprayer SL/No G: 100,000 No R:

30 0.975 15 0.00075 20,0 00 15

SL/G: 430 0.00419 3,600 3,100

Mixing/loading/applying liquid /WDG with handgun

sprayer SL/No G:

1300 No R:

3.9 0.0127 1,200 0.0000975 150,000 1,200

Loading/applying granules with backpack SL/No G: 155 No R: 23.8 0.00151 9,900 0.000595 25,000 7,100

Mixing/loading/applying liquid/WDG with backpack

sprayer Static Canal 100 SL/No G:

8260 No R:

2.58 2 lb ai/acre 2.5 acres 0.201 75

0.000161 93,000 75

SL/G: 8260 0.201 75 75

DL/G: 4120 0.1 150 150

Mixing/loading/applying SL/No G: No R: 2.44 6.1 0.00188 8,000 6.1Fluridone Human Health Risk Assessment DP No. 423464

Page 42 of 83 Table 9 .1. 2 . Occupational Handler Non

- Cancer Ex posure and Risk Estimates for the Registered Aquatic Uses of Fluridone

.

Exposure Scenario Crop or Target Level of

Concern Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit Exposure (μg/lb ai) 1 Maximum Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Combined

Mitigation

Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE
(LOC = 100) 8
liquid /WDG with

handwand sprayer 100,000 30

SL/G: 430 0.0105 1,400 1,200

Mixing/loading/applying liquid/WDG with handgun

sprayer SL/No G:

1300 No R:

3.9 0.0317 470 0.000244 61,000 470

Loading/applying granules with backpack SL/No G : 155 No R: 23.8 0.00378 4,000 0.00149 10,000 2,900

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ); Level of mitigation: SL/ No G = Single layer, no gloves. SL/G = Single layer, gloves. No R =

no respirator. Eng. Control = Engineering controls. Unit exposure for groundboom applicat ion used as surrogate for boat boom sprayer/spreader.

2 Based on regist ered labels

. 3 Exposure Science Advisory Council Policy #9.1 or as described in Section 6.1 above.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL ( 15 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0. 001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL ( 15 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL ( 15 mg/kg/day) ÷ Dermal Dose + Inhalation Dos e.Fluridone Human Health Risk Assessment DP No. 423464

Page 43 of 83 9.2 Short

- /Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop produc tion, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s deg radation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- application Risk

Proposed Cotton Use: As the proposed use is on pre

- plant or pre

- emergent cotton, no occupational post

- application dermal exposure to residues on foliage is expected.

Registered Aquatic Use: Since the currently registered uses of fluridone are in aquatic

environments , there are no occupational post

- ap plication activities which would result in occupational exposures from treated bodies of water. While scouting may include identifying aquatic weed re

- growth, this activity is not conducted until a few weeks after application. Therefore, occupational pos t

- application exposure of workers to previously treated water bodies / dry canals is expected to be negligible.

Restricted Entry Interval

Proposed Cotton Use: The REI specified on the proposed label is based on the acute toxicity of

fluridone. Fluridone is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

application exposures to fluridone . The REI of 24 hours on the pr oposed label for the cotton use is adequate and meets the minimum WPS requirements. It should be noted that the proposed label is a multiple active ingredient product, and should be considered when setting the REI for

the end

- use product.

Registered Aqu atic Use: As application to aquatic areas do not fall under the purview of WPS

and re

- entry exposure is considered to be negligible, an REI is not applicable for these uses.

9.2.2 Inhalation Post

- application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. Th e agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory PanelFluridone Human Health Risk Assessment DP No. 423464

Page 44 of 83 (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( h ttp://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration

Review , the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific

inhalation toxicolo gical studies) or further analysis is required for fluridone.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

10.0 Epidemiology

S. Recore a nd E. Evans, D426709, 6/2/15.

The current Incident Data System ( IDS ) analysis from January 1, 2010 through May 21, 2015 (Recore, 2015, D426709 ) , shows one incident reported involving fluridone in Main IDS involving multiple chemicals and two incidents reported to Aggregate IDS. There were no single chemical incidents reported to IDS. In addition, a query of SENSOR

- Pesticides 1998

- 2011

identifies the three c ases involving fluridone.

Based on the low frequency and low severity of incident cases reported for fluridone in both IDS

and NIOSH SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agenc y will continue to monitor the incident information and if a concern is triggered, additional analysis will be conducted.

11.0 References

Dole, T. D306456. Human Health Risk Assessment for Fluridone TRED. 17

- AUG

- 2015.

Gavelek, A. D43 1020

. Fluridone. Occupational and Residential Exposure Assessment for Registration Review and to Support the Registration of Proposed Use on Cotton. 06

- JAN

- 2016

.

Habiba, U., D42 7717 . Fluridone: Acute and Chronic Dietary Food and Drinking Water Exposure

and Risk Assessme nts for the Section 3 Registration Action. 20

- JAN

- 2016

.

Recore , S. a nd Evans , E. D426709 , Fluridone: Tier I Update Review of Human Incidental for

Draft Risk Assessment. 02

- JUN

- 2015

.

Drew D., Lloyd M., and Irwin W. D399892, Fluridone: ID#12AR01 Section 18 Emergency Exemption for Use on Cotton in Arkansas, South Carolina, Tennessee, and Florida. 05

- APR

2012

.

Tadayon, N. D319373. Revised Occupational a nd Residential Exposure Assessment and

Recommendations for t he Reregistration Eligibility Decision Document f or Endothall . 12

- AUG

2005.Fluridone Human Health Risk Assessment DP No. 423464

Page 45 of 83 Dole, T. D316596. 2,4

- D: 3 nd Revised Occupational and Residential Exposure and Risk Assessment and Response to Public Comments for the Registration Eligibility Decision (RED)

Document. 04

- MAY

- 2005.

Orrick, G. D423846. Fluridone: Drinking Water Exposure Assessment for Proposed New Use on

Cotton. 07

- MAY

- 2015.Fluridone Human Health Risk Assessment DP No. 423464

Page 46 of 83 Appendix A . Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.500) for food

- u se for fluridone are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 28

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no waived 1 yes

yes

yes

-

-
870.3700 Developmental Toxicity (rodent)

................................ ... 870.3700 Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . y es

yes

yes yes

yes

yes

870.4100 Chronic Toxicity (rodent)

................................ ............... 870.4100 Chronic Toxicity (nonrodent)

................................ ......... 870.4200 Oncogenicity (rat)

................................ .......................... 870.4200 Oncogenicity (mouse)

................................ .................... y es

yes

yes

yes yes

yes

yes

yes

870.5100 Mutagenicity

— Bacterial reverse mutation assay

.................... 870.5300 Mutagenicity

— gene mutation test

- mammalian

...................... 870.53 xx Mutagenicity

— chromosome aberration test

.......................... 870.53 xx Mutagenicity

— other

................................ ..................... y es

yes

yes

yes yes

yes

yes

yes 870.6100 Acute Delayed Neurotoxicity (hen)

................................ 870.6100 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200 Acute Neurotoxicity Screening Battery (rat)

.................. 870.6200 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

................................ ....... n o

no

yes waived 2

no -

- yes

-

no

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

no

yes

1 Waived by HASPOC (Leshin, 2015, TXR 0057221)

2 Waived by HASPOC (Rury, 2013, TXR 0056853)Fluridone Human Health Risk Assessment DP No. 423464

Page 47 of 83 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

- Test Substance

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 00135206 LD 50 = 10 g/kg IV

870.1200 Acute dermal [rabbit] 00082347 LD 50 > 2g/kg III

870.1300 Acute inhalation [rat] 00135206 LC 50 > 2.13 mg/L IV

870.2400 Acute eye irritation [rabbit] 00135206 Slight to moderate corneal dullness, iritis, & conjunctivitis w/clearing by 4 days II

870.2500 Acute dermal irritation [rabbit] 41424102 Non

- irrita nt IV

870.2600 Skin sensitization [guinea pig] 47425708 Not a sensitizer n/aFluridone Human Health Risk Assessment DP No. 423464

Page 48 of 83 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- Day oral toxicity (rat) MRID 00135209 (1978) Acceptable/Guideline 0, 330, 560, 1000, 1400, or 2000 ppm (males: 0, 30, 54, 106, 139, or 178.4; females: 0, 34, 53, 94, 126, or 202 mg/kg/day

based on initial food consumption) to Fischer

344 rats via diet for 90 days

NOTE: 81.9% of the

theoretical concentration was
present in the feed sample after 1 week storage. Therefore, corrected doses administered are 25, 44, 87, 114, or 146 m/k/d for males. NOAEL* = 25 mg/kg/day LOAEL = 44 mg/kg/day based on ↑absolute and relative liver (112

- 113% of controls) and relative kidney weights (106% of controls) (males only)

In males at 2 highest doses (114 and 146 m/k/d) ↑ centrilobular hypertrophy of the liver (1/15 of 114 m/k/d group) (12/15 of 146 m/k/d group)

* see note under doses

870.3100 90

- Day oral toxicity ( mouse ) MRID 00082342 (1978) Acceptable/Guideline 0, 62, 110, 200, 330, or 560 ppm (equivalent to 0, 9.3, 16.5, 30, 49.5 or 84 mg/kg/day based on 1 ppm = 0.15 mg/kg/day) to

ICR/SPR mice via diet for 90 days

NOTE: 50% of the

theoretical concentration was present in the feed sample after 3 months storage. Therefore, corrected doses administered are 4.6, 8.3, 15, 25, & 42 mg/kg/day

. NOAEL* = 15 mg/kg/day

LOAEL = 25 mg/kg/day based on ↑ centrilobular hypertrophy of the liver (incidences of centrilobular hypertrophy of the liver were 0/30, 1/28, 2/29, 3/29, and 6/30 cases in control, low

- , mid

- , high

- and highest

- doses)

NOTE: The dose related findings of this lesion

was also observed in other 90

- day mouse study with fluridone (MRID No. 82341)

* see note under doses

870.3150 13

- Week oral toxicity (dog) MRID 00082344 (1978) Unacceptable/Guideline 0, 50, 100, or 200 mg/kg/day to beagles via oral capsules NOAEL = 200 mg/kg/day (HDT)

LOAEL was not established

870.3200 21

- Day dermal toxicity (rabbit) MRID 00103299 (1981) Acceptable/Guideline 0, 192, 384 or 768 mg/kg/day to New

Zealand white rabbits for 21 days (6 hours/day and 5 days/week). Systemic: NOAEL = 768 mg/kg/day;

LOAEL was not established

Dermal: NOAEL < 192 (LDT) mg/kg/day; LOAEL = 192 mg/kg/day (LDT) based on transient, slight erythema in 9/10 animals accompanied by slight desquamationFluridone Human Health Risk Assessment DP No. 423464

Page 49 of 83 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3465 90

- Day inhalation toxicity (rat) Waived by HASPOC (TXR 0057221)

870.3700 Prenatal developmental in (rat) MRID 00159963 (1986) Acceptable/Guideline 0, 100, 300, or 1000 mg/kg/day to CD rats via oral gavage on gestation days 6 through 15 inclusive Maternal : NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on ↓ body weight gain and food consumption

Developm ental : NOAEL = 300 mg/kg/day LOAEL = 1000 mg/kg/day based on ↓ fetal body weight, ↑ rudimentary ribs and ↑ delayed ossification in sternebrae and pelvic girdle

870.3700 Prenatal developmental in (rabbit) MRID 00103302 (1980) Acceptable/Guideline 0, 125, 300, or 750 mg/kg/day to

Dutch Belted rabbits (15/sex/dose) via oral gavage on days 6

- 18 of gestation Maternal : NOAEL = 125 mg/kg/day LOAEL = 300 mg/kg/day based on ↓ body weight and food consumption and ↑ incidences of abortions (4/14 aborted betwee n days 20 and 25 of gestation)

Developmental : NOAEL = 125 mg/kg/day LOAEL = 300 mg/kg/day based on ↑ incidences of abortions (as above)

At 750 mg/kg/day, 6/11 aborted between days 20 and 25 of gestation

870.3800 Reproduction and fertility effects (rat)

3

- generation MRID 00103304 (1980) Acceptable/Guideline 0, 200, 650, or 2000 ppm

to Fischer 344 rats via diet

Calculated intake of fluridone during the growth phases over the 3 generations were 10.6

- 11.1, 35.5

- 36.6, or 111.9

- 112.3 mg/kg/day for

males and 1 2.4

- 13.2,

40.4

- 44, or 128

- 131.4 mg/kg/day for females. Parental and offspring : NOAEL > 112 mg/kg/day (HDT)

LOAEL was not established

Reproductive : NOAEL > 112 mg/kg/day (HDT)

LOAEL was not established

Developmental : NOAEL = 36 mg/kg/day LOAEL = 112 mg/kg/day based on ↓ pup weight (90.7% of controls; p<0.05; on lactation day 21 in F 2 generation )

870.4100 Chronic toxicity (rat) See guideline 870.4300

870.4100 Chronic Toxicity (Dog)

– 1 Year MRID 00103336 (1981) Acceptable/Guideline 0, 75, 150, or 400 mg/kg/day to beagles via gelatin capsules for 52

weeks NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on ↑ absolute liver weights and ↑ alkaline phosphatase activity (in female dogs)

.Fluridone Human Health Risk Assessment DP No. 423464

Page 50 of 83 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4200 Carcinogenicity (mouse)

- 2 year MRID
00103252/00103335 (1981

- 1982) Acceptable/Guideline 0, 33, 100, or 330 ppm for 2 years (equivalent to 0, 5, 15 or 50 mg/kg/day) to

ICR mice via diet for 104

weeks NOAEL = 15 mg/kg/day LOAEL = 50 mg/kg/day based on ↑ alkaline phosphatase activity (209% of c ontrols) and ↑ incidence of hepatocellular hyperplasia (2, 2, 4, and 6 cases in control, low

- , mid

- , & high

- doses)

* No increase in tumor incidence was found.

870.4300 Combined Chronic Toxicity/
Carcinogenicity (rat)

– 2 Years MRID
00103305/00103251 (1980) Acceptable/Guideline 0, 200, 650, 2000 ppm for 2 years (0,7.65, 25.15, 80.8 mg/kg/day in males and 9.17, 30.11, 97.00 mg/kg/day in females) to

Fischer 344 rats via diet

for 104 weeks NOAEL = 7.65 mg/kg/day

L OAEL = 25.15 mg/kg/day based on ↓ body

w eights (92% of controls; p<0.05), ↓ eosinophil

counts, ↑ absolute and relative liver and kidney weights

No increase in tumor incidence was found.

At 80.8 mg/kg/day (HDT) ↑ mortality (87% in ♂; 37% in ♀)
↑ chromorhinorrhea, anorexia, cloudy eyes, pale eyes ↓ body weight (59

- 66% in ♂; 81

- 89% in ♀) ↓ food consumption ↓ RBC counts, Hb, hematocrit, MCV, MCH ↓ lymphocyte and eosinophil counts ↑ nucleated erythrocytes, leukocyte & neutrophil counts ↑ total leukocyte count ↑ BUN, creatinine, bilirubin ↑ small testes, dose

- related trends in number of enlarged, pale and/or granular kidneys; opaque, cloudy, pale, red, or ulcerated eyes; & skin

nodules or masses. ↑ absolute and relative liver & kidney weights ↑ atrophy of testes, ocular keratitis, epidermal

inclusi on cyst
870.5100 Gene Mutation

(Ames Assay) MRID 00255339 Not mutagenic

870.5375 In vivo mammalian cytogenics

– sister

chromatid exchange in CHO MRID 00070942 Not mutagenic

870.5550 Unscheduled DNA damage/repair MRID 00070942 Not mutagenic

870.5550 Unscheduled DNA damage/repair MRID 00070942 Not mutagenicFluridone Human Health Risk Assessment DP No. 423464

Page 51 of 83 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.6200 Neurotoxicity screening battery

– Acute Neurotoxicity

– Rat
Crl:CD(SD) MRID 48939603 (2012)

0 (vehicle control), 125, 650, or 2000 mg/kg bw & observed for 14 days.

Dose volume = 5 m L/kg

98.02% a.i. NOAEL = 125 mg/kg bw/day

LOAEL = 650 mg/kg bw/day based anomalies

in open field

, and sensory parameters, and increased catalepsy time concurrent with

decreased mean ambulatory counts

.

870.6200 Neurotoxicity screening battery

– Subchronic Neurotoxicity (rat) Waived by HASPOC (TXR 0056853)

870.7485 Metabolism and pharmacokinetics

(rat) MRID
00103261/00103262 (1981) Unacceptable/Non

guideline

14 C

- labeled Fluridone ( 14 C

labeled in the 4

- position of the pyridinone ring) 10, 100, 250, 500 or 1000 mg/kg to Fischer 344 rats via single oral gavage - Readily absorbed and eliminated

- Total recovery of dosed radioactivity = 78

- 90% (3 days); 4

- 19 % (urine); 68

- 85 % (feces); Negligible% (tissues and carcasses); 66% (bile) Component in urine and feces

– not identified

- Major component (37% of dose) in bile

– not
identified

- Minor component in bile: Fluridone (8% of dose) 4

- hydroxyphenyl fluridone (6% of dose)

870.7485 Metabolism and pharmacokinetics (rat) MRID 44265101 (1997)

14 C

- labeled Fluridone

10 or 1000 mg/kg via single oral gavage - Majority of administered dose (79

- 92%) was eliminated in the feces, higher dose led to higher fecal elimination. Lower levels detected in the urine (9

- 15%). Most elimination occurred within 24 hours at low dose, 72 hours for high dose.

- Tissue residues w ere low (0.3

- 0.7%) but proportional to the dose, highest tissue residue levels in liver and kidney

- Eight (8) metabolites were identified from feces. Fluridone was extensively metabolized primarily through ring hydroxylation and N demethylation.

- Recovered >93% of administered dose in both genders

- minimal recovery from expired air

870.7600 Dermal absorption No study submitted
DAF = 39%

- an upper bound estimate of dermal absorption calculated from

the ratios the rabbit 21 day dermal toxicity study NOAEL & the rabbit developmental toxicity study LOAEL

.Fluridone Human Health Risk Assessment DP No. 423464

Page 52 of 83 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.7800 Immunotoxicity MRID 48939601 (2012) Acceptable/Guideline Fluridone (98.02%, a.i., Batch No.

MAR 1 1BE011) 0, 200, 400, or 1000 ppm (equivalent to 0, 43.5, 89.1, & 2 0 5.4 mg/kg bw/day, respectively) to

CD

- I female mice (10/group) in the diet for 28 days. Systemic: NOAEL = 205.4 mg/kg bw/day (HDT)

LOAEL was not established.

Immunotoxicity: NOAEL = 205.4 mg/kg bw/day

LOAEL was not established

.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Parent Compound Endpoint Selection

A.3.1.1 Acute Reference Dose (aRfD)

– General Population

Study Selected: Acute Neurotoxicity

- Rat
MRID No.: 48939603 Executive Summary : See Appendix A, Guideline [§ 870. 62 00] Dose and Endpoint for Risk Assessment: NOAEL = 125 mg/kg/day based o n decreased ambulatory counts and the prevalence of FOB anomalies in males and females observed at LOAEL

= 650 mg/kg/day. Uncertainty Factors: 100

– 10x for interspecies variation, 10x for intraspecies vari ation, and 1x FQPA SF Comments about Study/Endpoint: The adverse behavioral effects observed at 650 mg/kg/day in the ACN were in response to a single oral dose and thus were representative of an acute

exposure.

A.3.1.2 Acute Reference Dose (aRfD)

- Fem ales age 13

- 49 No acute dietary endpoint was identified that is specific to the female 13

- 49 subpopulation.

A.3.1.3 Chronic Reference Dose (cRfD )

Study Selected: 2 year carcinogenicity study

- mouse MRID No.: 00103252/00103335 Executive Summary : See Appendix A, Guideline [§ 870.4200] Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day. Uncertainty Factors: 100

– 10x for interspecies variation, 10x for intraspecies variation, and 1x FQPA SFFluridone Human Health Risk Assessment DP No. 423464

Page 53 of 83 Comments about Study/Endpoint: The 2 year carcinogenicity study chronicles adverse responses to a chronic oral exposure

, which is well suited for assessing the chronic dietary risks. A slightly lower NOAEL (8 mg/kg/day) was noted in the rat combined chronic toxicity/carcinogenicity study; however, this fact was considered to be due to dose

- selection (i.e. 15 mg/kg/day was not tested in this rat study). The NOAEL in the mouse study is p rotective of adverse findings noted in the rat combined chronic toxicity/carcinogenicity study, as well as the

rat 3

- generation reproduction study. The selected NOAEL is also protective of effects noted in the chronic dog study

.

A.3.1.4 Incidental Oral E xposure (Short

- and Intermediate

- Term)

Study Selected: 2 year carcinogenicity study

- mouse MRID No.: 00103252/00103335 Executive Summary : See Appendix A, Guideline [§ 870.4200] Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increa sed alkaline phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day. Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variation Comments about Study/Endpoint: The mouse chronic endpoint was appropriate for short

- and

intermediate

- term fluridone exposures, because mice were the most sensitive species in subchronic exposures, fluridone is rapidly metabolized and eliminated from the body at low doses (≤10 mg/kg), and no progression of toxicit y was evident when comparing the mouse subchronic toxicity study to the chronic toxicity study. Progression of toxicity was observed in rats; however, rat sensitivity was either less than (subchronic exposure) or similar (chronic exposure) to mice. The

POD from the 2 year mouse study was, therefore, both protective of the effects observed in rat and representative of short

- and intermediate

- term exposure durations.

A.3.1.5 Dermal Exposure (Short

- and Intermediate

- Term )

Study Selected: 2 year carcinogeni city study

- mouse MRID No.: 00103252/00103335 Executive Summary : See Appendix A, Guideline [§ 870.4200] Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day. Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variation Comments about Study/ Endpoint: The guideline dermal study was not used to set endpoints for the dermal assessment, because the study did not address concerns for sensitivity in the young described in the 3

- generation reproduction study. The systemic NOAEL from the dermal study is 384 mg/kg/day, but offspring toxicity is apparent at 112 mg/kg/day. The NOAEL from the 2 year mouse cancer study is 38.5 mg/kg/day after accounting for route

- to

- route extrapolation (DAF=39%), which is protective of the offspring effects. The mouse chro nic endpoint was appropriate for short

- and intermediate

- term fluridone exposures, because mice were the most sensitive species in subchronic exposures, fluridone is rapidly metabolized and eliminated from the body at low doses (≤10 mg/kg), and no progressi on of toxicity was evident when comparing the mouse subchronic toxicity study to the chronic toxicity study. Progression of toxicity was observed in rats; however, rat sensitivity was either less than (subchronic exposure) or similar (chronic exposure) to mice. The POD from the 2 year mouse study was, therefore, bothFluridone Human Health Risk Assessment DP No. 423464

Page 54 of 83 protective of the effects observed in rat and representative of short

- and intermediate

- term exposure durations.

A.3.1.6 Inhalation Exposure (Short

- and Intermediate

- Term)

Study Selected: 2 year carcinogenicity study

- mouse MRID No.: 00103252/00103335 Executive Summary : See Appendix A, Guideline [§ 870.4200] Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline phosphatase activity and increased hepatoce llular hyperplasia seen at LOAEL = 50 mg/kg/day. Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variation Comments about Study/Endpoint: A route specific study was not available for the inhalation assessment; however, HA SPOC approved substitution with an oral study because the calculated risk estimates using an oral endpoint and assuming 100% absorption were not of concern. The mouse chronic endpoint was appropriate for short

- and intermediate

- term fluridone exposures,

bec ause mice were the most sensitive species in subchronic exposures, fluridone is rapidly metabolized and eliminated from the body at low doses (≤10 mg/kg), and no progression of toxicity was evident when comparing the mouse subchronic toxicity study to the chronic toxicity study. Progression of toxicity was observed in rats; however, rat sensitivity was either less than (subchronic exposure) or similar (chronic exposure) to mice. The POD from the 2 year mouse study was, therefore, both protective of the effe cts observed in rat and representative of short

- and

intermediate

- term exposure durations.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

– Rat MRID 00135209

In a 90

- day oral toxicity study (MRID 00135209), fluridone (98.6% a.i.; Lot # 367

- Q52

- 59) was

administered to 15 SPF

- CD Fischer 344 rats/sex/dose in the diet at concentrations of 0, 330, 560, 1000, 1400, or 2000 ppm (equivalent to 0, 30, 54, 106, 139, or 178.4 mg/kg/day for males and 0, 34, 53, 94, 126, or 202 mg/kg/day for females based on initial food consumption).

There were no treatment

- related effects on survival, clinical signs, body weights, food consumption, and hematology or clinical chemistry parameters.

Treatment related effects were limite d to statistically significant increases in absolute and relative liver and kidney weights in both the male and female animals (Table 1). In male rats receiving the 560 ppm diets, absolute and relative liver weights (112

- 113% of controls) and

relative kid ney weights (106% of controls) were significantly increased.

In both males and females receiving the 1000 ppm diets and above, absolute and relative liver and kidney weights were significantly increased (105

- 124% of controls). Histological alterations were limited to liver centrilobular hypertrophy in male rats in the two highest doses groups (0/15 of control, 330, 560, and 1000 ppm groups, 1/15 of 1400 ppm and 12/15 of 2000Fluridone Human Health Risk Assessment DP No. 423464

Page 55 of 83 ppm groups). In this study, only tissues from liver and kidneys were examined microscopically because the high doses of fluridone (2000, 400 0, and 8000 ppm diets) had been shown to produce alterations in only liver and kidney in the previous study (MRID No: 00135208).

Stability study of fluridone in diets showed that only 81.9% of the theoretical concentration of fluridone in the 330 ppm (3 0 mg/kg/day) diet was present in the feed sample after 1week storage. The recovery of 81.9% of the test compound necessitated estimating a NOAEL for this study. The estimated NOAEL is 81.9% of 30 mg/kg/day or 25 mg/kg/day. Also, the estimated LOAEL

is 81 .9% of 54 mg/kg/day (560 ppm) or 44 mg/kg/day.

The LOAEL for fluridone in rats is 44 mg/kg/day based on increased absolute and relative liver weights and relative kidney weights. The NOAEL is 25 mg/kg/day. This 90

- day oral toxicity study is classified Acceptable/Guideline and satisfies the guideline requirements for a

90

- day oral toxicity study in the rat (OCSPP 870.3100; OECD 408).

870.3100 90

- Day Oral Toxicity

– Mouse MRID 00082342

In a 90

- day oral toxicity study (MRID No. 00082342), fluridone (9 7.8% a.i.; Lot # D36

- Y25

- 091) was administered to 15 ICR/SPR mice/sex/dose in the diet at concentrations of 0, 62, 110, 200, 330 or 560 ppm (equivalent to 0, 9.3, 16.5, 30, 49.5 or 84 mg/kg/day based on 1 ppm = 0.15 mg/kg/day).

There were no treatment

- rel ated effects on appearance, behavior, body weights or liver weights. Four males (2, 1, and 1 death in the 110, 200, and 330 ppm groups, respectively) and one female (in the 62 ppm group) died during the study but none of the deaths were attributed to trea tment. Treatment related effects were limited to increased incidence of hepatic centrilobular hypertrophy with increasing dose of fluridone in the male mice. The incidence of this lesion seen in the males was 1/28, 1/29, 3/29, or 6/30 in 110, 200, 330 or 560 ppm groups, respectively. The dose related findings of this lesion was also observed in other 90

- day study with fluridone (MRID No. 00082341) with the incidence of 5/30, 8/30, or 26/30 in 330, 560, or 1400 ppm groups, respectively.

Stability study of fluridone in diets showed that approximately 50% of the theoretical concentration of fluridone was present in the feed samples after 3 months storage. Therefore, the recovery of 50% of the test compound necessitated estimating a NOAEL for this study. The estimated NOAEL is 50% of 30 mg/kg/day (200 ppm diet) or 15 mg/kg/day. Also, the estimated LOAEL is 50% of 49.5 mg/kg/day (330 ppm diet) or 25 mg/kg/day.

The LOAEL for fluridone in mice is 25 mg/kg/day based on increased incidence of hepatic
centrilo bular hypertrophy. The NOAEL is 15 mg/kg/day.

This 90

- day oral toxicity study is classified Acceptable/Guideline and satisfies the guideline requirements for a 90

- day oral toxicity study in the mouse (OCSPP 870.3100; OECD 408). The study was reported in 1978. The diet analysis indicated that the concentration of the test compound in treatment diet decreased overti me. The report did not show how rapidly the concentration of the test diet deteriorated. Using the decrease found at 3 month (50% drop) wasFluridone Human Health Risk Assessment DP No. 423464

Page 56 of 83 a conservative approach. In addition, the report did not indicate how frequently diet was prepared and how long i t was stored prior to offering to the test mice.

870.3150 90

- Day Oral Toxicity

– Dog MRID 00082344

In a 90

- day oral toxicity study (MRID No. 00082344), fluridone (98.6% a.i. Lot # 597

- B29

- 200C) was administered to 4 beagle dogs/sex/dose in capsules at doses of 0, 50, 100, or 200 mg/kg/day. No adverse, treatment

- related effects were observed on survival, clinical signs, body weight, body weight gain, food consumption, hematology, bone marrow analysis, urinalysis, organ weights, gross pathology, or micro scopic pathology.

The LOAEL for fluridone in dogs is not established and the NOAEL is equal or greater than 200 mg/kg/day (HDT).

This 90

- day oral toxicity study is classified Acceptable/Non

- Guideline and does not satisfy the guideline requirements for a 90

- day oral toxicity study in the dog [OCSPP 870.3150 (§82

- 1b)]. Although the results reported were valid for the doses tested, the study is classified non

- guideline because no adverse effects were observed at the high dose (200 mg/kg/day). Dose selecti on for
the 90

- day study was based on a slight body weight reduction observed at 200 mg/kg/day in a range finding study. This minor body weight effect is not indicative of an adverse response to treatment and suggests the animals could have tolerated a high er dose in the 90

- day study. However, another 90

- day guideline non

- rodent study is not required at this time because the toxicological data requirements are satisfied by the 1

- year feeding study in dogs (MRID No. 00103336). [NOTE: This study was classifie d as minimum (acceptable) in the previous review (TXR No. 000824).]

870.3200 21/28

- Day Dermal Toxicity

– Rat MRID 00103299

In a 21

- day dermal toxicity study (MRID No. 00103299 ), groups of New Zealand white rabbits (5/sex/dose group) received F luridone 4AS (Lot No.: #X

- 36339; purity: 44.5% a.i.) by dermal application at doses of 0, 192, 384 or 768 mg/kg/day for 21 days (6 hours/day and 5 days/week).

No adverse, treatment

- related effects were observed on survival , clinical signs, body weight, body wei ght gain, food consumption, hematology, clinical chemistry, organ weights, or gross or histological pathology.

Localized dermal reactions included the following:

Animals in the 192 mg/kg/day group (20% formulation) showed transient, slight erythema in

9/ 10 animals, accompanied by slight desquamation.

Animals in the 384 mg/kg/day group (40% formulation) showed moderate, well

- defined erythema, slight edema and mild desquamation, and epidermal fissures in 3/10 rabbits.

Animals in the 768 mg/kg/day grou p (80% formulation) showed moderate to severe erythema with epidermal fissures in 8/10 rabbits, accompanied by slight edema.Fluridone Human Health Risk Assessment DP No. 423464

Page 57 of 83 Differences in the dermal response between abraded and non

- abraded skin were not statistically significant.

The LOAEL for systemic toxicity was not established. The NOAEL was 768 mg/kg/day.

The LOAEL for dermal toxicity was 192 mg/kg/day b ased on transient, slight erythema in 9/10 animals accompanied by slight desquamation

. T he NOAEL for dermal toxicity was

not established.

This 21

- day dermal toxicity study is cla ssified Acceptable/Guideline and satisfies the guideline requirement for a 21

- day dermal toxicity study (82

- 2) in the rabbit.

870.3465 90

- Day Inhalation

– Rat

Waived by HASPOC (TXR 0057221)

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat MRID 00159963

In a developmental toxicity study (MRID No. 00159963), 25 presumed pregnant Crl:CD ® (SD) rats per group were administered Fluridone (purity: 99.5%; batc h/lot No.: 414DT4) by oral gavage in 10% acacia solution at doses of 0, 100, 300, or 1000 mg/kg/day on gestation days (GD) 6

- 15, inclusive. On GD 20, dams were sacrificed and necropsied, and gravid uterine weights and the numbers of fetuses, early and lat e resorptions, total implantations and corpora lutea were recorded. All fetuses were weighed, sexed, and subjected to external examination followed by fresh dissection. Approximately one

- half of the fetuses from each litter terminated

on GD 20 were fixed in Bouin’s solution for visceral examination, and the remaining fetuses were eviscerated and processed for skeletal examination. Maternal Toxicity

One dam (#2061) on 300 mg/kg/day was found dead on GD 10 (after receiving 4 doses) apparently as a conse quence of an injury during dosing. Autopsy revealed dark

- red, collapsed lungs, surrounded by fibrin and fluid. There were 15 implantation sites in utero

.

In mid

- and high

- dose groups, dose

- related significant decreases in the body weight gain and

food consumption were recorded during the first half of the treatment period (days 6 to 10), but weight gain rebounded during the latter half (days 11 to 15) of the treatment period. In the high

dose group, adjusted overall net weight gain (minus gravid uteri ne weight) during the post

treatment period remained significantly depressed (20% less than controls). In addition, higher incidences of alopecia was observed only in the 1000 mg/kg/day group (5 rats vs. 0, 1, and 1 rat at 0, 100, and 300 mg/kg/day, respe ctively).Fluridone Human Health Risk Assessment DP No. 423464

Page 58 of 83 Necropsy findings in sacrificed dams (hydronephrosis, empty stomach and gastrointestinal tract, infantile uterine horn, etc.) were evenly distributed and of low incidence in all groups with no compound relationship.

Therefore, the LOAEL for maternal toxicity was 300 mg/kg/day based on reduced body weight gains and food consumption; NOAEL for maternal toxicity was 100 mg/kg/day.

Devel opmental Toxicity

There were no differences between the control group and the all treated groups for number of females pregnant, corpora lutea, number of implant per pregnancy, % of live fetuses or % resorptions. No dead fetuses were observed in any grou p.

At 1000 mg/kg/day, mean fetal weight (males = 3.25 g; females = 3.04 g) was significantly decreased as compared with controls (male= 3.66 g; females 3.53 g). In female fetuses at 1000 mg/kg/day, rudimentary ribs (T

- 13, T

- 14, L

- 1) in seven litters an d delayed ossification of sternebrae and pelvic girdle in two litters were observed.

Renal cavitation and ureter dilatation were reported at a higher incidence than controls in the

mid

- and high

- dose groups, but these fetal variations have been observed i n higher incidences in controls from other studies conducted by the same laboratory. One high

- dose fetus had a shortened right hindlimb (micromelia) and associated skeletal defects, while two high

- dose fetuses from a separate litter had hernias and one of these had hypoplastic lungs.

Therefore, the LOAEL for developmental toxicity was 1000 mg/kg/day based on decreased fetal weight, increased incidences of rudimentary ribs, and delayed ossification in sternebrae and pelvic girdle; NOAEL for developmental toxicity was 300 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the requirements for a developmental toxicity study [OCSPP: 870.3700a (83

- 3a)] in rats.

870.3700b Prenatal Developmental Toxicity Study

– Rabbit MRID 00103302

In a developmental toxicity study (MRID No. 00103302), fluridone (lot no.:X

- 29478; purity: 99.5% a.i.) in 10% acacia solution was administered daily by oral gavage to pregnant female Dutch Belted rabbits (15/sex/dose) on days 6

- 18 of gestation at dose levels of 0, 125, 300, or 750 mg/kg/day. The rabbits were observed for signs of toxicity and body weight and food consumption values were recorded. On day 28 of gestation, the rabbits were sacrificed and necropsied and the numbers of fetuses, early and late re sorptions, total implantations and corpora lutea were recorded. The fetuses were removed, weighed, sexed, and examined for external anomalies. They were then processed for visceral or skeletal evaluation.

Maternal Toxicity

No deaths were observed in th e control and 125 mg/kg/day (LDT) groups. One female in the 300 mg/kg/day group was found dead on day 23 of gestation. An acute upper respiratory tractFluridone Human Health Risk Assessment DP No. 423464

Page 59 of 83 infection and focal acute pneumonia were observed at necropsy. Two animals were found dead on day 23 in the 750 mg/kg/day group. No diagnosis was reported for one; the other female was diagnosed as having an acute upper respiratory tract infection and acute pneumonia. No other signs of toxicity were observed in any of the surviving animals during the st udy.

There were no differences between the control group and low

- dose group for the body weight gain and mean food consumption during the treatment period.

In the mid

- dose group, a slight loss in the body weight, the body weight gain, and mean food

con sumption during the treatment period were slightly reduced when compared to the controls, however, the difference was not statistically significant. At the mid

- and high

- dose levels

, increased incidence of abortions was also seen (detailed below).

The me an body weight changes during the treatment period at high dose

- level was significantly reduced (

- 2.3%; p<0.05) when compared to the controls (+4.9%). Mean food consumption during the treatment period and post

- treatment period of the high

- dose animals were 62% and 77% of the control values, respectively.

In addition, treatment related increased incidences of abortions was observed at both the mid

and high

- doses. Since maternal toxicity was also observed at these doses (reduced body weight

and food co nsumption), the increased incidence of abortions seen at mid

- and high

- dose levels was considered to be secondary to the maternal effects.

Therefore, the LOAEL for maternal toxicity was 300 mg/kg/day based on increased incidence of abortions and slight de creases in the body weight and food consumption; NOAEL for maternal toxicity was 125 mg/kg/day.

Developmental Toxicity

No dead fetuses were observed in any group and the mean fetal body weights of all treatment groups were comparable to the control group. A dose

- related decrease in the ratio of live fetuses to implantation sites was evident. The ratios were 0.96, 0.95, 0.80, and 0.65 for control, low

- , mid

- and high

- dose groups, respectively.

The reproduction findings showed that 4 of 14 mid

- dose and 6 of 11 high

- dose pregnant rabbits aborted between days 20 and 25 of gestation. The number of high

- dose rabbits successfully maintaining pregnancy until day 28 of gestation was reduced by deaths and abortions when compared to the control group. Thir teen of the 13 control rabbits reached day 28 of gestation, whereas, only 5 of the 11 high

- dose rabbits were still pregnant by day 28 of gestation. The mean number of resorptions/litter was increased two and one half fold when the mid

- dose (1.5) was

compar ed to the controls (0.6), however, this difference was not statistically significant. At high

dose, the mean number of resorptions/litter (3.0) was significantly increased (p<0.05) when compared to the controls (0.6).

One control and one high

- dose fetus each had multiple abnormalities, however, these abnormalities were considered spontaneous and not related to fluridone. In addition, the controlFluridone Human Health Risk Assessment DP No. 423464

Page 60 of 83 fetus was observed to have hair lip, omphalocelle, and absent forepaws and hindlimbs. The high

- dose fetus was observed to have exencephally, omphalocele, rudimentary ear, and rudimentary forelimbs without digits. No visceral abnormalities were observed in either the control or treatment groups. An increase in the percentage of fetuses with 13 th ribs was observe d in the high

- dose level as compared to controls, however, the percentage of fetuses with 13 th ribs was comparable to the historical controls. There were increased incidences of unidentified thickened rib and sternebral variations in the high

- dose level.

Therefore the LOAEL for developmental toxicity was 300 mg/kg/day based on incr eased incidences of abortions; NOAEL for developmental toxicity was 125 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the requirements for a

devel opmental toxicity study [OCSPP: 870.3700b (83

- 3b)] in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat MRID 00103304

In a 3

- generation reproduction study (MRID 00103304), fluridone (99.5% a.i., lot # X

- 29478)

was administered to 25 Fischer 344 rats/sex/dose in the diet at concentrations of 0, 200, 650, or 2000 ppm. The mean calculated intake of fluridone during the growth phases over the 3 generations were 10.6

- 11.1, 35.5

- 36.6, or 111.9

- 112.3 mg/kg/day for males a nd 12.4

- 13.2, 40.4

- 44, or 128

- 131.4 mg/kg/day for females. Two litters were produced by each generation, and the animals were administered test or control diet continuously for at least 10 weeks prior to mating, throughout mating, gestation, lactation, an d until necropsy. The F 2 generation parents were mated three times and histopathologic examination was conducted on selected F 3b progeny and the teratology phase of the study was conducted on the F 3 c litters. The F 3 a pups were terminated at weaning becau se of poor viability in all treatment groups, however, the report stated that “No cause was determined for the loss of significant numbers of F 3 a pups between days 1 and 7 postpartum.”

For low

- and mid

- dose F 0 females, there were two deaths resulting from the room temperature reaching 38 0 C. One control F 2 female died, but cause of death was not evident. There were no

treatment

- related effects on body weights and food consumption during the growth phase in any of the three generations. Also, fluridone di d not produce clinical signs of toxicity in the animals in any of the generation. The absence of parental toxicity indicates that optimal dietary levels of the test material were not used, thus compromising the sensitivity of the test.

The maternal body weights and body weight gains of the fluridone

- treated females were comparable to those of the control females on days 0 to 20 of gestation and on day 21 of lactation during all generations (F 1 , F 2, F 3 a, and F 3 b). Also, in the teratology phase (F 3 c) of the study, no dose

- related differences were observed in the body weights at days 0, 7, 14, and 20 of gestation, nor were any observed for the weight gains from day 0 to day 20 of gestation. The
LOAEL for materna l toxicity was not determined; NOAEL f or maternal toxicity was equal or greater than 2000 ppm (112 mg/kg/day, HDT)

.Fluridone Human Health Risk Assessment DP No. 423464

Page 61 of 83 The test chemical did not significantly affect any of the reproductive parameters. Therefore, the NOAEL for reproductive toxicity is equal to or greater than 2000 ppm ( 112 mg/ kg/day, HDT) and the LOAEL is not established.

Fluridone significantly depressed the body weights (90.7% of controls; p<0.05) on lactation day 21 of the 2,000 ppm F 2 pups. A comparison of the pup weight gain from day 1 to day 21 of

lactation indicated a dose

- related trend toward decreased weight gain among the fluridone

treated pups, however, the differences were not statistically significant. Therefore, the NOAEL for offspring toxicity is 650 ppm ( 36 mg/kg/day) and the LOAEL is 2000 ppm ( 112 mg/kg/day , HDT) based on decreased pup weight (on lactation day 21 ).

For developmental toxicity phase of the study, F 3 c developmental toxicity data shows that there were no evidence of embryolethality, altered fetal growth, or developmental alteration. Therefore, the LOAEL for developmenta l toxicity was not determined; NOAEL for developmental toxicity was equal or greater than 2000 ppm (112 mg/kg/day, HDT)

.

This study is classified as Acceptable/Guideline and satisfies the guideline requirements for a

2

- generati on reproductive study in the rat ( OCSPP 870.3800; OECD 416). However, the teratology phase of the study is classified as Unacceptable/Guideline and does not satisfy the requirements for a developmental toxicity study [ OCSPP : 870.3700 (83

- 3a)] in rats beca use the highest dietary level failed to produce maternal toxicity. A separate acceptable guideline rat developmental study (MRID 00159963) was submitted that satisfied the guideline requirement for a developmental toxicity study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat MRID 00103305/00103251

There were three studies conducted concurrently and reported as combined chronic/carcinogenicity study (MRID 00103305 and 00103251). For these three studies fluridone (Lot No: D36

- Y25

- 091 ; purity: 97.2% a.i.) was administered to Fischer 344 rats (75/sex/dose) in the diet at levels of 0, 200, 650, or 2000 ppm. Corresponding daily intake of test

material for the two

- year studies were 0, 7.65, 25.15, or 80.80 mg/kg/day in males and 0, 9.17, 30.11, or 97.00 mg/kg/day in females. The first study was a one year study consisting of 15

rats/sex/dose and the other two studies were 2

- year study each consisting of 30 rats/sex/dose/study.

None of the animals in the one

- year study died prior to the 1 2

- month sacrifice. For the 2

- year studies, the mortality rate through week 77 was 10% or less for all test groups. However, from week 78 (18 months) through the remainder of the study, increase in mortality occurred in high

dose males (87% vs 20

- 32% in t he other male groups). Mortality rates among female groups were similar to the control until the last month of the study, when an increase in mortality occurred among high

- dose females (37% vs 23% in the controls).

No treatment

- related effect was seen at 200 ppm (7.65 mg/kg/day).Fluridone Human Health Risk Assessment DP No. 423464

Page 62 of 83 The mid

- dose males (25.15 mg/kg/day) at final sacrifice exhibited decreased body weights (92% of controls; p< 0.05), decreased eosinophil counts, and increased absolute and relative liver and kidney weights as compared to controls.

In the high

- dose animals (80.8 mg/kg/day) , treatment related toxicity observed includes decreased body weights and food consumption and pale eyes and thin appearance in both sexes, increased incidences of chromorhinorrhea, anorexia, and cloudy eyes in males.

At final sacrifice, the mean erythrocyte counts, hemoglobin, mean corpuscular hemoglobin

concentration and hematocrit values fr om high

- dose males were significantly lower (p<0.05) than control values. In high

- dose females, only hemoglobin levels was significantly lower than

the control values.

The high

- dose males had increased levels of nucleated erythrocytes and neutrophil coun t and a decreased levels of lymphocyte and eosinophil counts when compared to controls at study termination. Also, statistically significant increases in total leukocyte count were noted in high

dose males and females.

BUN and creatinine levels in both sexes were significantly higher than the controls.

Necropsy findings observed at final sacrifice were increased incidence of small testes noted in the high

- dose group. The mean testes weight of high

- dose males was lower than control values,

but the rela tive testes weight was not significantly different from controls. In addition, there was

an increased dose

- related trends in number of enlarged, pale and/or granular kidneys (in males and females). In addition, there was increased number of opaque, cloud y, pale, red, or ulcerated eyes (in males) and increased number of skin nodules or masses (in females).

At interim and final sacrifices, both absolute and relative liver and kidney weights and relative spleen weights in the high dose males and females w ere significantly higher than controls.

Examination of the renal cortex by electron microscopy showed necrosis in albumin precipitate in 1/4 high

- dose male and necrosis in 2/4 high

- dose females.

Histopathologic findings showed that incidence of atrophy o f the testes and ocular keratitis were increased in high

- dose males. Incidences of epidermal inclusion cysts (non

- neoplastic retention of keratin in the skin) were increased in treated animals of both sexes. Also the incidences of skin papillomas were i ncreased in treated animals of both sexes, however, the skin papillomas do not represent an oncogenic response to fluridone treatment because of the following reasons:

1) statist ical analyses were conflicting; 2) skin papillomas do not represent a life

- threatening lesion; 3) the majority of “masses” grossly identified in this study were minute in size (“wart

- like”); and 4) there is no hint these could have undergone malignant transformation.Fluridone Human Health Risk Assessment DP No. 423464

Page 63 of 83 The NOAEL for systemic toxicity was 200 ppm (7.65 in males and 9.17 mg/kg/day in females). The LOAEL for systemic toxicity was 650 ppm (25.15 in males and 30.11 mg/kg/day in females) based on decreased body weights, decreased eosinophil counts, and

increa sed absolute and relative liver and kidney weights.

The tumor issue of this study was peer reviewed by the HED Cancer Assessment Review Committee (TXR 007726, July 15 and October 7, 1985). The committee evaluated the available

data and concluded that the data did not provide evidence for the carcinogenicity of fluridone in

rats.

Dosing was considered adequate in this study based on increased mortality, decreased body weight and food consumption, increased liver and kidney weights, changes in hematology parameters, changes in clinical chemistry parameters (increased BUN, creatinine, bilirubin), increased incidence of chromorhinorrhea, anorexia, and cloudy and pale eyes observed at high

dose (80.8 mg/kg/day). In addition, there were changes in morphology of erythrocytes (increased incidences of nucleated erythrocytes, leukocyte and neutrophil counts), changes in total and differential leukocyte counts (increased leukocyte counts and decreased lymphocyte and eosinophil counts). Also, fluridone treatment a t high

- dose resulted in increased incidences of small testes and enlarged, pale and/or granular kidneys. Also increased incidences of opaque, cloudy, pale, red, or ulcerated eyes, skin nodules or masses, atrophy of testes, ocular keratitis, and epidermal inclusion cyst observed at high

- dose.

This study is classified as Acceptable/Guideline and satisfies the Subdivision F guideline requirements for a combined chronic toxicity/carcinogenicity study (83

- 5) in rats.

870.4100b Chronic Toxicity

– Dog MRID 001 03336

In a chronic toxicity study (MRID No. 00103336), 4 beagle dogs/sex/dose were orally administered fluridone (98.1% a.i.; Lot # D36

- Y93

- 107) in gelatin capsules at doses of 0, 75, 150, or 400 mg/kg/day for 52 weeks.

There were no deaths during the study and no treatment

- related ophthalmic findings were noted at the termination of the study. No differences that could be attributed to compound administration were evident in any of the urinalysis, hematologic parameters , and gross or histopathologic examinations. Also, fluridone did not induce hepatic mixed

- function oxidase activity. Dose

- related emesis occurred in females only (0/4 controls, 2/4 low

- dose, 3/4 mid

dose, and 4/4 high

- dose), however, sporadic occurrence of this finding precludes assessment of its biological significance.

No treatment

- related effects were found in the low

- dose animals.

In the 150 mg/kg/day group , body weight gain was slightly lower (4

- 6%; statistically not significant) in males as com pared to the controls over the last two months of the study.

In the 400 mg/kg/day group , body weight gain was slightly lower (6

- 10%; statistically not significant) in males and females as compared to the controls over the last two months of theFluridone Human Health Risk Assessment DP No. 423464

Page 64 of 83 study. A lso, alkaline phosphatase activity in female dogs was statistically significantly elevated (approximately 2

- 3 times of control) beginning at the 5 th week and continuing to the study termination. No increase in alkaline phosphatase activity was found in th e males. Additional findings in the high

- dose females were significantly increased absolute liver weights (118% of controls, p<0.05) and increase in the relative liver weights (not statistically significant). A potential hepatotoxic effect of fluridone i n this study is consistent with previous findings: elevated alkaline phosphatase activity was observed at 200 mg/kg (HDT) in a 3

- month oral toxicity study in dogs and elevated alkaline phosphatase activity and increased relative liver weights were observed at 400 mg/kg (HDT) in a 2 week oral pilot study in dogs.

The LOAEL is 400 mg/kg/day based on significant increases in absolute liver weights and increases in alkaline phosphatase activity in female dogs. The NOAEL is 150 mg/kg/day. (In the original DE R, the LOAEL was conservatively estimated at 150 mg/kg/day based on the slight weight loss in males and the trend towards increased alkaline phosphatase activity (120

- 170% of the control values) in females.

This chronic study in the dog is classified Acce ptable/Guideline and satisfies the guideline requirement for a chronic oral study in the dog [OCSPP 870.4100b; OECD 452].

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- Rat

Study is detailed under guideline 870.4100a

870.4200b Carcinogenicity (feeding)

– Mouse MRID 00103252/00103335

There were three studies conducted concurrently and reported as carcinogenicity study (MRID 00103335 and 00103252). In these 3 studies, fluridone (Lot No: D36

- Y25

- 091; purity: 97.2% a.i.) was admi nistered to ICR mice (120/sex/dose in controls; 80/sex/dose in treated groups) in the diet at levels of 0, 33, 100, or 330 ppm (equivalent to 0, 5, 15 or 50 mg/kg/day based on a conversion factor of 1 ppm = 0.15 mg/kg/day). The first study was a one year study consisting

of 15 mice/sex/dose. In the 2 two

- year studies, the control groups consisted of 60 mice/sex/study and each of the dosed groups consisted of 40 mice/sex/study.

Mortality among the control and dosed animals in the one

- and two

- year studies were similar.

No treatment

- related effect was seen at 33 (low

- dose) and 100 (mid

- dose) ppm

. Overall, no

dose

- related ch anges in hematology parameters were apparent for 300 (hi gh

- dose) ppm males and females. For high

- dose females of the first 2

- year study (M

- 9407), hematology data showed statistically significant decreases in hemoglobin, packed cell volume, and monocyte counts compared to controls. For high

- dose males, a signi ficant decrease in the lymphocyte counts and a significant increase in the neutrophil counts were observed. However, the se parameters were
not reduced in the second 2

- year study (M

- 9417).Fluridone Human Health Risk Assessment DP No. 423464

Page 65 of 83 The high

- dose males showed statistically significant increases in alkaline phosphatase (134 and 209% of controls at 12 and 24 months, respectively) (study M

- 9407). The combined data

from 2 two

- year studies indicated a significant increase (157% of controls) in alkaline phosphatase activity in the high

- dose group males as compared to controls.

Absolute organ weights for males and females showed no compound

- related effects at interim and final sacrifices. In the high

- dose females, relative liver weights were significantly higher

than controls at interim sacrifice but this was not supported by the absolute liver weights.

Gross examination showed no compound related effects in any tissue. Histopathological examination at final sacrifice showed a slight but significant (p<0.05) increase in hepatocellular hyperplasia fo r the high

- dose males (2, 2, 4, and 6 cases in control, low

- , mid

- , and high

- doses). A slight increase in hepatic focal atypia (not defined in the final study report) was also noted for high

- dose females (0, 1, 2, and 2 cases in control, low

- , mid

- , and h igh

- doses).

The report indicated an increased incidence of fibrosarcomas of the skin in the high

- dose females. The tumor issue of this study was peer reviewed by the HED Cancer Assessment Review Committee (TXR 007726, July 15 and October 7, 1985). The c ommittee concluded that the available data did not provide evidence for the carcinogenicity of fluridone in mice.

The NOAEL for systemic toxicity was 100 ppm (15 mg/kg/day). The LOAEL for systemic toxicity was 3 30 ppm (50 mg/kg/day) based on an increas e in alkaline phosphatase activ ity
and increased incidence of hepatocellular hyperplasia

.

There was not a treatment

- related increase in tumor incidence in any treated groups when compared to controls.

Dosing was considered adequate in this study based on increase in alkaline phosphatase activ ity

and increased incidence of hepatocellular hyperplasia for the high

- dose males.

This study is classified as Acceptable/Guideline and satisfies the Subdivision F guideline requirements for a carcinogenicity study (83

- 2) in mice.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, gene mutation

MRID 00255339 Not mutagenic

Cytogenetics

Guideline 870.5375, In vivo mammalian cytogenics

– sister chromatid exchange in CHO

MRID 00070942 Not mutagenic

Other GenotoxicityFluridone Human Health Risk Assessment DP No. 423464

Page 66 of 83 Guideline 870.5550, Unscheduled DNA damage/repair

MRID 00070942 Not mutagenic

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

Not required

870.6200 Acute Neurotoxicity Screening Battery MRID 48939603

In an acute neurotoxicity study (MRID 48939603)

, groups of 6

- week

- old Crl:CD(SD) rats ( 10 /sex/dose) were given a single oral gavage dose of fluridone (98.02% a.i.; Lot no. MAR11BE011) in 5% Acacia in deionized water at doses of 0 (vehicle control), 125, 650, or 2000 mg/kg bw and observed for 14 days. Functional observation battery ( FOB ) and locomotor activity data were recorded for all animals prior to the initiation of dose administration, on Day 0 at the time of peak effect (approximately 4 hours following dose administration), and on Days 7 and 14. Animals were sacrificed on Day 15 and perfused in situ . Brain weights and brain dimensions were recorded. A neuropathologic al evaluation of selected tissues from the central (CNS) and peripheral nervous systems was performed on 5 animals/sex in the control and 2000 mg/kg groups.

Treatment with fluridone did not affect clinical signs, mortality, gross necropsy findings, neuropathology, brain weight, or brain dimensions.

Dose

- related changes in FOB parameters were observed in males and females at 125, 650 and 2000 mg/kg bw of f luridone. These changes were transient, occurring only on Day 0 , and often disappeared by Day 7 or 14.

Anomalies in a multitude of FOB parameters was observed in the 2000 mg/kg group . Home cage observations revealed clonic convulsions (repetitive movement of mouth and jaws) (2 males; 5 females) and cage biting (2 males; 3 females). Open

- field ob servations included gait abnormality (hunched body : 2 males; 5 females) and one male also exhibiting bizarre/stereotypic behavior (repetitive turning of head from side to side). Sensory observations revealed a number of animals had no reaction or response to approach (3 rats each), touch (3 rats each), startle (4 males; 2 females), and/or tail pinch (4 males; 3 females). Air righting reflex was also impaired (slightly uncoordinated: 2 males; 2 females; landing on their side: 1 male; 2 females). One high

dose female exhibited no hindlimb extension. Physiological observations found a longer catalepsy time in males only (2.4 vs. 0.4 seconds for controls), mainly due to 2 rats with long

times. Females had reduced body temperature compared to controls (35.8 vs. 37.1°C for

controls ) . Lastly, motor activity was reduced. Although mean cumulative total activity counts

were not affected , mean cumulative ambulatory activity counts were decreased (p<0.05) in males ( 325 vs. 500 counts for controls) and females (521 vs. 828 counts for controls )

.Fluridone Human Health Risk Assessment DP No. 423464

Page 67 of 83 Similar effects were observed in male and female rats at 650 mg/kg bw on Day 0 but generally

occurred at a much lower incidence and were mostly limited to minor FOB anomalies . These

effects included : clonic convulsions (1 female), cage biting (1 female)

, gait abnormality (hunched body; 1 male)

, no response/reaction to approach (4 males; 1 female) , touch (4 males; 1 female) , startle ( 3 males), and/or tail pinch ( 3 males), and abnormal righting reflex ( landing on its side; 1 female). Males from the 650 mg/kg/day dose group also exhibited longer catalepsy time outside the historical control range, which was considered a more serious neurotoxic response relative to the other FOB anomalies. Both males and females experienced a r eduction in mean ambulatory counts concurrent with the behavioral anomalies

.

C hanges in FOB parameters on Day 0 were also noted in males and females at 125 mg/kg bw

a lthough many of the chan ges, similar to the 650 mg/kg/day dose group, occurred at a lo w incidence and were relatively minor anomalies . These effects included gait abnormality (hunch ed body) and uncoordinated air right ing reflex ( both in same female) , and no reaction/response to approach (4 males; 1 female) , touch (3 males; 2 females) , start le ( 2 males), and/or tail pinch (1 male). At the 125 mg/kg/day dose, cumulative total and ambulatory motor activity counts were

not affected.

Male and female rats from all dose groups exhibited depressed body weight gain (5

- 25% less than controls) duri ng the two weeks after treatment. The impact of depressed body weight gain on absolute body weight was negligible ( all dose groups were comparable to controls on Day 0, 7 and 14); therefore, the body weight gain depression was not considered adverse. Food consumption was not recorded.

The changes in FOB parameters in combination with significant depression of cumulative ambulatory activity counts was considered evidence of an adverse response at the mid and high

doses. In the absence of a corroborative effect on motor activity, the FOB effects at the low dose

were not considered adverse because the effects were limited to minor behavior aberrations not anticipated to impact quality of life and were of low incidence.

The LOAEL is 650 mg/kg bw based on decreased ambulatory counts and the prevalence of
FOB anomalies in males and females

. The NOAEL is 125 mg/kg/day.

This neurotoxicity study is classified as A cceptable/Guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats ( OCSPP 870.6200; OECD 424).

870.6200 Subchronic Neurotoxicity Screening Battery

Waived by HASPOC (TXR 0056853)

870.6300 Developmental Neurotoxicity Study

Not required

A.4.8 MetabolismFluridone Human Health Risk Assessment DP No. 423464

Page 68 of 83 870.7485 Metabolism

– Rat MRID 00103261/00103262

MRID 00103261

In a rat metabolism study (MRID No. 00103261), Fischer 344 rats (5 animals/sex/group) received a single oral gavage dose of 14 C

- labeled fluridone (Lot No. 553

- 897

- 200; purity not provided) at 10, 100, 250, 500 or 1000 mg/kg for urine and fecal elimination study. For both biliary elimination (13 males) and tissue distribution (15 animals/sex) studies, Fischer 344 rats

receive d a single oral gavage dose of 14 C

- labeled fluridone at 100 mg/kg/day.

The urine and fecal elimination study indica tes that fluridone is rapidly and almost completely absorbed into the systemic circulation and eliminated in both the male and female rats within 3 days. The total radioactivity recovered within 3 days after dosing in the urine and feces were 78

- 90% and 8 7

- 97% of administered dose in males and females, respectively. Doses of 1000 mg/kg/day were eliminated less rapidly than doses between 10 and 500 mg/kg/day. Over a 3

- day period, the radioactivity recovered in the urine was 4

- 14% and 11

- 19% of the dose in males and females, respectively. The radioactivity recovered in feces was 72

- 79% and 68

- 85% of the dose in males and females, respectively.

The tissue distribution study showed that there was no indication of bioaccumulation in any tissue or organ after administration of each of the five dosage regimens. The study showed that the highest tissue to plasma ratios were found in liver, kidney, ileum, and colon. The tissue to plasma ratios following 4, 24, and 96 hours after dosing ranged 11

- 43 for liv er, 6

- 18 for kidney,

2

- 15 for ileum, and 1

- 9 for colon. Nearly 90% of the radioactivity present in tissues was cleared by 96 hours after dosing.

The bile contained 61% of the total radioactivity administered 2 days after dosing.

MRID No. 00103262

In a biliary elimination study and identification of bile metabolites (MRID No. 00103262), Fischer 344 rats (5 males) receive d a single oral gavage dose of 14 C

- labeled fluridone at 100 mg/kg/day. An average of 44 and 66% of the administered dose was eliminate d in rat bile within 24 and 48 hours after dosing, respectively. The radioactivity eliminated in the bile consisted of unidentified highly polar metabolites (55.5% of the total bile radioactivity; approximately 37% of administered dose), fluridone (12%; 8 % of dose) and the 4

- hydroxyphenyl fluridone (9%; 6% of dose). The identity of fluridone and the 4

- hydroxyphenyl fluridone were confirmed by gas chromatography

- mass spectrometry (GC

- MS).

The unidentified metabolites (55.5% of the total bile radioactivi ty) consisted of the following components: polar metabolites remained at the origin of the chromatograms in the 2nd ethyl acetate extract (6% of the bile radioactivity) and 3 rd ethyl acetate extract (15.7% of the bile radioactivity) and radioactive compone nts in the aqueous phase (33.8% of the bile radioactivity) which were not hydrolyzed by 2N HCl.Fluridone Human Health Risk Assessment DP No. 423464

Page 69 of 83 The results of these studies indicated that 14 C

- labeled fluridone was absorbed, and much of it was metabolized. Majority of the radioactivity eliminated via feces (approximately 70%). No tissue

accumulation was seen.

These combined rat metabolism studies are classified U nacceptable/Non

- guideline. Although the results of these studies provide good understanding of metabolism of this chemical most of

the adm inistered radioactivity in feces was not identified. [Comments: It is noted that in the previous DERs, the major metabolism study (MRID: 00103261) was classified as core minimum. The biliary elimination study (MRID: 00103262) was classified as supplement ary because polar metabolites which constituted the bulk of the metabolites were not identified.]

870.7485 Metabolism

– Rat MRID 44265101

Male and female rats (5/sex) were administered either a single oral low dose of labeled fluridone

at a nominal dose of 10 mg/kg, a multiple oral low dose of unlabeled fluridone at 10 mg/kg once daily for 14 days followed by a single labeled fluridone dose at 10 mg/kg on day 15, or a single oral high dose of labeled fluridone at a nominal dose of 1000 mg/kg. Two ani mals of each gender were administered a dose of 1% vehicle (carboxymethyl cellulose) to act as controls. A majority of the administered dose in the single oral low dose, multiple oral low dose, and single oral high dose was eliminated in feces (79

- 92%). Lo wer levels were detected in urine (9

- 15%, sum of urine and cage rinse) over 7 days following dosing. Most of the elimination occurred

within the first 24 hours post

- dose for the single and multiple oral low dose regimens, whereas complete elimination of th e single oral high dose required 72 hours. Excretion profiles of urine and feces were considered dose dependent because a significantly higher amount of fecal elimination occurred at the single high dose. The profiles did not vary significantly between

gen ders. Although tissue residues were low (~0.3

- 0.7%), the highest residues levels were most often found in liver and kidney. Tissues from animals receiving the high dose showed proportionally higher residue levels than those from the other two groups. Overa ll recovery of the administered dose amounted to between 93% and >100% for all three dose groups. The major components in the excreta were fluridone (single low dose = 4.49%, multiple low dose = 5.61%, single high dose = 56.6%) and fluridone metabolites (s ingle low dose = 62.9%, multiple low dose = 55.9%, single high dose = 32.4%) produced primarily by ring hydroxylation and N

demethylation. Fourteen metabolites were identified in the feces and urine including: Parent compound (3.89

- 60.26%), Non

- polar [(Flu ridone) 2

- S

- SO)] (3.18

- 6.05%), Fluridone (CF 3 Ø

- SH) (0.23

- 2.99%), Fluridone

- [Ø

- (OH

- SCH 3 )] (0.20

- 2.76%), Fluridone

– (Ø

- SH) (0.26

- 2.67%), Desmethyl

- Fluridone (2.62

- 4.42%), (Ø

- OH)

- Fluridone (1.55

- 5.09%), Fluidone

- (Ø

- OH) (0.35

- 2.39%), (Ø

- OH)

- Desmethyl

- Fluridone (1.03

- 7.92%), (CF 3 Ø

- OH)

- Desmethyl

- Fluridone (1.34

- 2.94%), (CF 3 Ø

- OH, Ø

- OH)

- Fluridone (0.77

- 4.89%), polar metabolites (4 isomeric products

4.34

- 19.56%), and two unidentified metabolites (1 st metabolite

– 4.63%

- 9.81%, 2 nd metabolite

– 1.06

- 9.34%). Percentage range covers all dose groups from both male and female excreta.

This metabolism study is classified as A cceptable/Guideline and satisfies the guideline requirement for a metabolism study in rats (OCSPP 870.7485; OECD 417).

870.7600 Dermal Absorption

– R atFluridone Human Health Risk Assessment DP No. 423464

Page 70 of 83 No study submitted. A 39% dermal absorption factor was estimated from the ratios of LOAELs of a 21 day dermal toxicity study & a developmental toxicity study in rabbits.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity MRID 48939601

In an immunotox icity study (MRID 48939601), fluridone (98.02%, a.i., Batch No. MAR11BE011) was administered to CD

- 1 female mice (10 /group ) in the diet at concentrations of 0, 200, 400, or 1000 ppm (equivalent to 0, 43.5, 89.1, and 205.4 mg/kg bw/day, respectively)

for 28 days. A concurrent positive control group received the basal diet, but was administered 50 mg/kg bw/day cy clophosphamide monohydrate (CPS) by IP inject tion on study days 24

- 27. During the study, c linical signs of toxicity were monitored daily, and body weight and food consumption were monitored weekly. On Day 24, a ll mice were sensi tiz ed with 1 × 10 8 sheep red blood cell (sRBC) . The mice were sacrificed on day 28, the spleen, thymus, and liver removed and weighed, and spleen cel ls suspension were prepared for plaque forming cells ( PFC )

assay

.

There were no treatment

- related effects on clinical signs, morbidity, mortality, body weights, or organ weights (liver, spleen and thymus) in any treated group compared to the control.

The systemic NOAEL was 1000 ppm (equivalent to 205.4 mg/kg bw/day) , the highest dose tested; the LOAEL was not identified.

There were no statistically s ignificant differences in treated groups when compa re to the vehicle control group for PFC responses. High inter

- individ ual variability was noted in all the treatment groups as well as in the control group. Evaluation of the individual animal data of this study did not show any trend or distribution that would demonstrate significant s uppression of anti

- SRBC

PFC response. Positive control group had st atistically significant decrease o f the antibody

response

. This confirmed the ability of the test system to detect immuno

- suppressive effects and confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database

for fluridone does not reveal any evidence of immunotoxicity. The overall weight of evidence suggests that the chemical does not directly target the immune sy stem. Under HED guidance a NK cell activity assay is not required at this time.

The immunotoxicity NOAEL was 1000 ppm (equivalent to 205.4 mg/kg bw/day) ; the
LO AEL was not identified.

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline requirement for an immunotoxicity study ( OCSPP 870.7800) in mice.Fluridone Human Health Risk Assessment DP No. 423464

Page 71 of 83 Appendix B

. Physical/Chemical Properties

Table B1. Physico

- Chemical Properties

Parameter Value Reference

Molecular Weight 329.3 Molecular Formula: C 18 H 14 F 3 NO

Water solubility (20°C) 8.3 mg/L (20°C) MRID 49368504

Solvent solubility (20°C to 25°C) 5

- 10 g/L NIH

Vapor pressure (25°C) <9.77 x 10

- 8 torr (25°C) Tomlin, 2003 (The Pesticide Manual, 13th Ed. p.476, BCPC Publications, Hampshire)

Dissociation constant, pKa None at pH 1.0

- 12.9 MRID 49368504
Octanol/water partition coefficient, log K OW (25°C) 2.54 MRID 49368504

Soil Half

- life (or other relevant information from EFED Drinking water assessment) No evidence of degradation MRID 49385701Fluridone Human Health Risk Assessment DP No. 423464

Page 72 of 83 Appendix C

. Review of Human Research

Human Studies Review This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; and the Residential SOPs; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included re view by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency

website 10

.

10 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

- exposure

data and http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- post

application

- exposureFluridone Human Health Risk Assessment DP No. 423464

Page 73 of 83 Appendix D . International Tolerances and MRLs

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex

40 CFR 180.420: (a) General. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only the sum of fluridone, 1

- methyl

- 3

- phenyl

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1H)

- pyridinone, and its bound residues, calculated as the stoichiometric equivalent of fluridone None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex Crayfish 0.5

Fish 0.5

US 40 CFR 180.420 Canada Mexico 1 Codex (2) Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only fluridone, 1

- methyl

- 3

- phenyl

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1 H )

- pyridinone None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex
Cattle, fat 0.05 Cattle, kidney 0.1 Cattle, liver 0.1 Cattle, meat 0.05 Cattle, meat byproducts 0.05 Egg 0.05 Goat, fat 0.05 Goat, kidney 0.1 Goat, liver 0.1 Goat, meat 0.05 Goat, meat byproducts 0.05 Hog, fat 0.05 Hog, kidney 0.1 Hog, liver 0.1 Hog, meat 0.05 Hog, meat byproducts 0.05 Horse, fat 0.05 Horse, kidney 0.1
Horse, liver 0.1
Horse, meat 0.05 Horse, meat byproducts 0.05

Milk 0.05 Poultry, fat 0.05 Poultry, kidney 0.01 Poultry, liver 0.01 Poultry, meat 0.05 Poultry, meat byproducts 0.05 Sheep, fat 0.05 Sheep, kidney 0.1Fluridone Human Health Risk Assessment DP No. 423464

Page 74 of 83 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex Sheep, liver 0.1 Sheep, meat 0.05 Sheep, meat byproducts 0.05 Completed: M. Negussie; 07/23/15

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex
40 CFR 180.420:

P lant/Livestock : 1

- methyl

- 3

- phenyl

- 5

- (3

- (trifluoromethyl)phenyl)

- 4(1 H )

- pyridinone None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex Cotton, undelinted seed 0.1 Cotton, gin byproducts 0.1 Completed: M. Negussie; 05/18/2015

1 Includes only commodities of interest for this action. Tolerance values are HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Fluridone Human Health Risk Assessment DP No. 423464

Page 75 of 83 Appendix E. NMF Exposure and Risk Assessment

Summary

N

- methyl f ormamide (NMF) is a possible degradate of fluridone . Under laboratory conditions, using a light source that does not mimic the sun, photolysis of fluridone in water led to the formation of NMF. The Agency is unaware of any evidence that supports the formation of NMF in the environment from photolysis of fl uridone. However, a screening assessment is considered for fluridone using extremely conservative assumptions: 100% conversion of fluridone to NMF, the possibility that NMF can reach the ground water, and a 10X uncertainty factor due to the lack

of toxicit y data.

Fluridone is registered for use as an aquatic herbicide and is proposed for pre

- emergent treatment of cotton. These treatments may result in fluridone reaching surface water sources of drinking water. There is a potential for fluridone to be fo und in ground water via several natural processes. There may also potential for residential post

- application exposure to NMF while swimming in fluridone

- treated water.

The toxicology profile for NMF is limited to one developmental study in rats and rabb its that was reported in the literature , and substantial uncertainty surrounds the toxicity of NMF in mammals. Toxicological endpoints were selected for acute (female s 13

- 49 years old ) and chronic dietary exposures, and for short

- term residential incidenta l oral, dermal, and inhalation exposures. An acute RfD was established for the female 13

- 49 subpopulation based on decreased fetal viability and body weight and increased incidence of skeletal malformations . This acute effect was not appropriate for the ge neral population. For all other endpoints, the POD was 10 mg/kg/day (NOAEL) and the LOAEL was 75 mg/kg/day for rats and 50 mg/kg/day for rabbits based on based on body weight loss during gestation . The same three uncertainty factors were applied to each ex posure scenario: 10x for interspecies extrapolation (UF A ), 10x for intraspecies variation (UF H ), and 10x to account for the lack of NMF toxicity studies (FQPA SF).

Acute and chronic dietary exposure assessment s were conducted for NMF in drinking water ; N MF is not a residue of concern in food. Estimated drinking water concentrations ( EDWCs )
assumed 100% conversion of fluridone to NMF. There were no acute or chronic dietary risk estimates of concern for NMF in drinking water for any of the population subgro ups assessed (all risk estimates <100% aPAD or cPAD).

The proposed new use on cotton is not anticipated to result in residential exposures to NMF; however, the existing aquatic uses of fluridone could result in exposure to NMF for swimmers.

The residenti al post

- application exposure assessment assessed adults and children (3 to < 6 years old) who may be exposed to NMF while swimming in treated water (dermal, inhalation and incidental ingestion exposure routes) . There were no risks of concern for swimmers for the individual routes (i.e., all NMF MOEs ≥ 1000). Since all the routes of exposure are based on the same effect, the exposures can be combined across routes

. The combined MOEs for adults and children are also not of concern (i.e., all NMF combined MOEs ≥ 1000).Fluridone Human Health Risk Assessment DP No. 423464

Page 76 of 83 There are no acute or chronic residential exposure scenarios; therefore t he acute and chronic aggregate risk s for NMF are equivalent to the acute and chronic risk estimates , respectively . The

acute and chronic dietary exposure estimates for NMF in drinking water are not of concern (risk
estimates are < 100% of the aPAD or cPAD for all population subgroups assessed).

Short

- term aggregate risk assessments for NMF are necessary, since there is potential for residential exposure to NMF from t he aquatic uses. For the short

- term aggregate risk assessment, potential residential exposures (dermal, inhalation, and incidental ingestion exposure from swimming in treated waters) were combined with drinking water exposures. The short

- term aggregate MOE s for NMF for adults and children are greater than the level of concern (LOC = 1000 ) and are, therefore, not of concern. Intermediate

- term residential exposures are not likely because of the intermittent residential exposure to NMF ; therefore, an intermed iate

- term aggregate risk assessment is not required.

Occupational exposure to NMF is not anticipated since NMF only forms in water due to the photolysis of fluridone. In addition, the proposed use on cotton is for pre

- plant or pre

- emergent use; therefor e, occupational post

- application dermal exposures to residues on foliage are not expected. For the aquatic uses of fluridone, occupational post

- application exposure of workers to previously treated water bodies is expected to be negligible, since post

- app lication activities are not anticipated for occupational workers post

- treatment.

Chemical Identity

Table E.1. Test Compound Nomenclature

Chemical Structure

Common name N

- methyl formamide (NMF) CAS registry number 123

- 39

- 7

CAS name Formamide, N

- methyl

Table E.2. Summary of Toxicological Doses and Endpoints for NMF for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure
Scenario Point of Departure Uncertainty

Factors RfD, PAD,
Level of
Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (Females 13

- 49 years) NOAEL =

10 mg/kg/day UF A =10x

UF H =10x

UF DB =10x a RfD = 0.01 mg/kg/day Developmental Toxicit y in Rats and Rabbits

LOAEL = 75 mg/kg/day for rats and 50 mg/kg/day for rabbits based on decreased fetal viability and weight; increased incidence o f

skeletal malformationsFluridone Human Health Risk Assessment DP No. 423464

Page 77 of 83 Table E.2. Summary of Toxicological Doses and Endpoints for NMF for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure
Scenario Point of Departure Uncertainty

Factors RfD, PAD,

Level of
Concern for

Risk
Assessment Study and Toxicological Effects

Acute Dietary ( General population including

infants and children) A dose and endpoint were not selected for this population group because the acute effects observed in the developmental toxicity study in rats and rabbits were not applicable to the general population.

Chronic Dietary NOAEL=

10 mg/kg/day UF A =10x

UF H =10x

UF DB =10x c RfD = 0.01 mg/kg/day Developmental Toxicity in Rats and Rabbits

LOAEL = 75 mg/kg/day for ra ts and 50 mg/kg/day for rabbits based on body weight loss during gestation

Incidental Oral

Short

- Term NOAEL=

10 mg/kg/day UF A =10x

UF H =10x

UF DB =10x MOE = 1000 Developmental Toxicity in Rats and Rabbits
(same as chronic dietary)

Dermal

Short

- Term NOAEL=

10 mg/kg/day UF A =10x

UF H =10x

UF DB =10x MOE = 1000 Developmental Toxicity in Rats and Rabbits
(same as chronic dietary)

Inhalation

Short

- Term NOAEL=

10 mg/kg/day UF A =10x

UF H =10x

UF DB =10x MOE = 1000 Developmental Toxicity in Rats and Rabbits
(same as chronic dietary)

Cancer (oral, dermal, and inhalation) No evidence of mutagenicity or carcinogenicity was observed in the single study available.

P oint of Departure ( POD ) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. N OAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (int raspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Dietary Exposure and Risk AssessmentFluridone Human Health Risk Assessment DP No. 423464

Page 78 of 83 NMF remains a residue of concern in drinking water unless acceptable aqueous photolysis data

are submitted that demonstrate otherwise ( Orrick; 2015, D423846 ). Concentrations of NMF

were found in an aqueous photolysis study (Mosier and Saunders, 1982; MRID 125743) where up to 74% of the applied amount of fluridone was converted to NMF

. However, t his study utilized lamps that are known to produce irradiation different from that of natural sunlight

. Consequently, this study w as classified as unacceptable. NMF may or may not be a photodegradate in water under natural conditions . F luridone did not readily photolyze on soil. If

NMF forms, it will do so in surface water and potentially migrate to ground water. NMF appears to be stable to photolysis and hydrolysis, since it was found to increase in concentration at study termination, 30 days after treatment

.

Concentrations of NMF in drinking water were estimated assuming NMF conversion efficiency of 100%, and by adjusting for the ratio of the fluridone molecular weight of 329 to the NMF molecular weight of 59. The drinking water residue for NMF was assumed to be 0.006 ppm [(34 or 32 ppb * 59 g/mol) / 329 g/mol]. This estimate of NMF concentration is very conservative

, because it is unknown if exposure occurs at all, the conversion rate of fluridone to NMF is unknown, and the highest drinking water estimate for fluridone was used (which occurs in ground water).

A cute and chronic dietary exposure assessment s w ere performed for NMF using the DEEM

FC ID model. Only drinking water was included in the dietary analysis; NMF is not a residue of

concern in food. Acute dietary (drinking water) risks were determined f or females 13

- 49 years old (the only population subgroup for which an acute toxicological endpoint was identified). The resulting risk estimate was 3.3% of the aPAD at the 95 th percentile of exposure. Chronic dietary (drinking water) risks were determined fo r the general population and all population subgroups. The most highly exposed population subgroup was infants (<1 year old), with a risk estimate of
3.2 % of the cPAD. These risk estimates are all well below 100% of the PAD and are not of

concern. The ris k estimates are summarized in table E.3 below.

Table E.3. Summary of Dietary Drinking Water Exposure and Risk Estimates for

NMF

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/da y) % cPAD

General U.S. Population N/A N/A 0.000126 1.3

All Infants (<1 year old) N/A N/A 0.000324 3.2*

Children 1

- 2 years old N/A N/A 0.000181 1.8

Children 3

- 5 years old N/A N/A 0.000153 1.5

Children 6

- 12 years old N/A N/A 0.000110 1.1

Youth 13

- 19 years old N/A N/A 0.000092 < 1

Adults 20

- 49 years old N/A N/A 0.000125 1.3
Adults 50+ years old N/A N/A 0.000124 1.2Fluridone Human Health Risk Assessment DP No. 423464

Page 79 of 83 Table E.3. Summary of Dietary Drinking Water Exposure and Risk Estimates for

NMF

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/da y) % cPAD

Females 13

- 50 years

old 0.000332 3.3 0.000125 1.2

*The highest exposed population subgroup

Residential Exposure and Risk Assessment

Since NMF may be formed in water via photolysis, residential exposures to NMF are anticipated for the aquatic uses of fluridone in order to be protective of possible exposures . No NMF exposure is anticipated from the proposed agricultural uses of fluridone. Post

- application exposure to NMF in aquatic environments (i.e., adult and child swimmers) has been assessed according to HED’s November 2015 Draft Aquatic Use SOP

. The quantitative exposure/risk

assessment for residential post

- application exposures is based on the following scenarios:

• Adults and children (3 to <6 years old) swimming in treated water (dermal , inhalation and incidental ingestion)

Residential Post

- A pplication Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each assumption and factor is detailed in the Draft 2015 Aquatic Use SOP.

Application Rate: C oncentrations of NMF were estimated assuming NMF conversion efficiency

of 100 %

, and by adjusting for the ratio of the fluridone molecular weight of 329 g/mol to the NMF molecular weight of 59 g/mol

. A maximum concentration of 150 ppb (0.15 mg/L) was assumed for the fluridone assessment, therefore, a concentration of 27 ppb (0.027 mg/L) was used to assess aquatic exposure to the degradate, NMF.

Exposure Duration: Residential exposure is expected to be short

- term in duration.

Residential Post

- A pplication Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential non

- cancer post

- application exposure and dose can be found in the Draft November 2015 Aquatic Use SOP.

Combining Non

- Cancer Exposure and Risk Estimates Since dermal, inhalation and incidental oral exposure routes share a common to xicological endpoint, exposure estimates have been combined for those routes.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates For NMF, the combined MOE for adult swimmers is 4, 4 00,000 and for child swimmers is 530,000; the refore, there are no risk estimates of concern (LOC = 1000).Fluridone Human Health Risk Assessment DP No. 423464

Page 80 of 83 Table E.4

. Residential Post

- application Non

- cancer Exposure and Risk Estimates for NMF.

Lifestage Post

- application Exposure

Scenario Application

Rate 1 Dose (mg/kg/day) 2 MOEs 3 Combined Routes (X indicates

included in Combined MOE) Combined MOEs (LOC = 1000) Use Site Route of Exposure

Adult

Aquatic Dermal

27 ppb (0.027 mg/L) 2.7E

- 7 36,000,000 X

4,400,000 Inhalation 2.06E

- 8 490,000,000 X

Incidental Ingestion 1.96E

- 6 5,100,000 X

Child (3 to

<6 years

old) Dermal 9.7E

- 7 10,000,000 X

530,000 Inhalation 1.22E

- 7 82,000,000 X

Incidental Ingestion 1.78E

- 5 560,000 X

1 Based on application of fluridone and conversion to NMF.

2 Dose (mg/kg/day) equations :

• Inhalation Dose (mg/kg/day) = [Concentration in water (0. 027 mg/L) * Dimensionless Henry’s law constant ( 8.21 E

- 07 ) * CF (1000

L/m 3 ) * IR (0.64 m 3 /hr for adults and 0.32 m 3 /hr for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW ( 69 kg

for adult s and 19 kg for children).

• Dermal dose (mg/kg/day) = [Concentration in water (0. 027 mg/L) * Permeability constant ( 0.0 0039 ) * Surface area (19,500 cm 2 for adults and 7,600 cm 2 for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW ( 69 kg for adults and 19 kg for children).

• Incidental ingestion dose (mg/kg/day) = [Concentration in water (0. 027 mg/L) * Ingestion rate (0.05 L/hr) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (69 kg for adults and 19 kg for childre n).

3 MOE = POD (10 mg/kg/day) ÷ Dose (mg/kg/day).

4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

Table E. 5 reflects the residential risk estimates that are recommended for use in the aggregate

assessment for NMF

.

• The recommended residential exposure for use in the adult aggregate assessment reflects dermal and incidental oral exposures from post

- application ex posure to aquatic applications

.

• The recommended residential exposure for use in the child (3 to <6 years old) aggreg ate
assessment reflects dermal and incidental oral exposures from post

- application exposure

to aquatic applications.

Table E. 5 . Recommend ations for the Residential Exposures for the NMF Aggregate Assessment.

Lifestage Exposure
Scenario Dose (mg/kg/day) 1 MOE (LOC = 1000) 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Swimming 2.7E

- 7 2.06E

- 8 1.96 E

- 6 2.3E

- 6 36,000,000 490,000,000 5,100,000 4, 4 00,000

Child (3 to <6 years old) Swimming 9.7E

- 7 1.22E

- 7 1. 7 8E

- 5 1.9E

- 5 10,000,000 82,000,000 560,000 530,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed . Total = dermal + inhalation + incidental oral (where applicable)

. 2 MOE = the MOEs associated with the highest residential doses . Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MOE), where applicable

.Fluridone Human Health Risk Assessment DP No. 423464

Page 81 of 83 Aggregate Exposure and Risk Assessment

Acute: There are no acute residential exposure scenarios ; therefore, t he acute aggregate risk is equivalent to the acute dietary risk estimate . The acute dietary risk estimate for NMF in drinking

water is not of concern to HED (<100% a PAD) for females 13

- 49 years old (the only population subgroup for which an acute toxicological endpoint has been identified)

.

Short

- term: Short

- term aggregate risk assessments for NMF are neces sary since there is potential for residential exposure to NMF f rom the aquatic uses, and data are presented in Table

E.6

. For the short

- term aggregate risk assessment, potential residential exposures were

combined with average drinking water exposures. See Table E.5 for information on the

residential risk estimates that are recommended for use in the aggregate assessment for NMF.

The short

- term residential exposure estimates were aggregated with the chronic dietary (drinking water) exposure to provide a worst

- case estimate of short

- term aggregate risk for adults and

children. The short

- term aggregate MOEs for adults and children are greater than the LOC of 1000 for NMF, and are therefore not of concern.

Table E.6. Short

- Term Aggregate Risk Calculations for NMF

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average Drinking

Water Exposure mg/kg/day 3 Residential Exposure mg/kg/day 4 Total Exposure mg/kg/day 5 Aggregate MOE (food, water, and residential) 6

Adult 10 1000 0. 01 0.000 125 0.0000023 0.000 127 7 9 ,000

Child 10 1000 0.01 0.000324 0.000019 0.000343 29,000

1 LOC based on the standard inter

- and intra

- species uncertainty factors , in addition to a 10x database uncertainty factor; total UF

= 100 0

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Chronic D ietary (drinking water) exposure for females (13

- 49 years old) and all infants less than 1 y ea rs old (see Table E.3. ). .

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure], where applicable.

5 Total Exposure = Average Drinking Water Exposure + Residential Exposure.

6 Aggregate MOE = [NOAEL (10 mg/kg/day)/ (Total Exposure, mg/kg/day)]

.

Intermediate

- term: Intermediate

- term residential exposures are not likely because of the

intermittent residential exposure to NMF ; t herefore

, an intermediate

- term aggregate risk assessment is not required.

Chronic: There are no chronic residential exposure scenarios; therefore, the chronic aggregate

risk is equival ent to the chronic dietary risk estimate . The chronic dietary (drinking water) risk estimates for NMF are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups

.

Occupational Exposure and Risk Assessment

Occupational exposure to NMF is not anticipated since NMF is only suspected to form in w ater due to the photolysis of fluridone. In addition, the proposed use on cotton is for pre

- plant or pre

emergent use ; therefore, occupational post

- application dermal exposures to residues on foliageFluridone Human Health Risk Assessment DP No. 423464

Page 82 of 83 are not expected. For the aquatic uses of fluridone, o ccupational post

- application exposure of workers to previously treated water bodies is expected to be negligible

, since post

- application

activities are not anticipated for occupational workers post

- treatment.Fluridone Human Health Risk Assessment DP No. 423464

Page 83 of 83 Addendum: Executive Summary f or the Toxic ity Study

Prenatal Developmental Toxicity Study

– Rat and Rabbit MRID 49719001

Kelich SL, MD Mercieca, RC Pohland. 1995. Developmental toxicity of N

- methylformamide administered by gavage to CD rats and New Zealand white rabbits

. Fundam. Appl. Toxicol. 27(2) : 239

- 246. MRID 49719001.

N

- Methylformamide (NMF) is a metabolite of dimethylformamide (DMF), a solvent with wide applications in the chemical industry. The potential developmental toxicity of NMF was

evaluated in CD rats and New Zealand white rabbits. Pregnant rats and rabbits were dosed once daily by gavage on Gestation Days 6

- 15 and 6

- 18, respectively. Doses for rats were 0, 1, 5, 10, or 75 mg/kg; doses for rabbits were 0, 5, 10, or 50 mg/kg. Cesarean sections were performed on rats

and rabbi ts on Gestation Days 20 and 29, respectively. No treatment

- related maternal deaths or clinical signs occurred in either species. Body weight gain and food consumption were depressed in rats given 75 mg/kg and rabbits given 50 mg/kg. Fetal viability was red uced at 75 mg/kg in rats and at 50 mg/kg in rabbits. In rats, a significant increase in the incidence of malformations including cephalocele and sternoschisis was observed in fetuses from the 75 mg/kg group. In addition, a developmental delay was indicated by reduction of fetal weight and by a significant increase in the occurrence of incomplete ossification of various skeletal structures. In the rabbit, fetal body weight was reduced at 50 mg/kg. Malformations observed at 50 mg/kg included gastroschisis, ce phalocele, domed head, flexed paw, and skull and sternum anomalies. The

lowest

- observed

- adverse

- effect levels for maternal and developmental toxicity in the rat and rabbit were 75 and 50 mg/kg, respectively. The no

- observed

- adverse

- effect level for materna l and developmental toxicity in the rat and rabbit was 10 mg/kg.